Biological, diagnostic and therapeutic relevance of the MET receptor signaling in head and neck cancer

JPT-06679; No of Pages 13 Pharmacology & Therapeutics xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera

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Associate Editor: Beverly Teicher

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Lluís Nisa a,b,⁎, Daniel Matthias Aebersold a,b, Roland Giger c, Yitzhak Zimmer a,b,⁎,1, Michaela Medová a,b,1

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Biological, diagnostic and therapeutic relevance of the MET receptor signaling in head and neck cancer☆,☆☆

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a r t i c l e

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Keywords: Head and neck cancer MET receptor tyrosine kinase Targeted therapy Prognostic impact Treatment resistance

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Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern, Switzerland Department of Clinical Research, University of Bern, 3010 Bern, Switzerland Department of Otorhinolaryngology-Head & Neck Surgery, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern, Switzerland

a b s t r a c t

Head and neck cancer constitutes the 6th most common malignancy worldwide and affects the crucial anatomical structures and physiological functions of the upper aerodigestive tract. Classical therapeutic strategies such as surgery and radiotherapy carry substantial toxicity and functional impairment. Moreover, the loco-regional control rates as well as overall survival still need to be improved in subgroups of patients. The scatter-factor/hepatocyte growth factor receptor tyrosine kinase MET is an established effectors in the promotion, maintenance and progression of malignant transformation in a wide range of human malignancies, and has been gaining considerable interest in head and neck cancer over the last 15 years. Aberrant MET activation due to overexpression, mutations, tumor-stoma paracrine loops, and cooperative/redundant signaling has been shown to play prominent roles in epithelial-to-mesenchymal transition, angiogenesis, and responses to anti-cancer therapeutic modalities. Accumulating preclinical and translational evidence highly supports the increasing interest of MET as a biomarker for lymph node and distant metastases, as well as a potential marker of stratification for responses to ionizing radiation. The relevance of MET as a therapeutic molecular target in head and neck cancer described in preclinical studies remains largely under-evaluated in clinical trials, and therefore inconclusive. Also in the context of anti-cancer targeted therapy, a large body of preclinical data suggests a central role for MET in treatment resistance towards multiple therapeutic modalities in malignancies of the head and neck region. These findings, as well as the potential use of combination therapies including MET inhibitors in these tumors, need to be further explored. © 2014 Published by Elsevier Inc.

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1. 2. 3. 4. 5. References

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biological aspects of mesenchymal-to-epithelial transition signaling in head and neck cancer . . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic relevance of mesenchymal-to-epithelial transition in head and neck cancer . Therapeutic relevance of mesenchymal-to-epithelial transition in head and neck cancer Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: CSC, cancer stem-like cell; DDR, DNA damage response; ECM, extracellular matrix; EGFR, epidermal growth factor receptor; Egr-1, early growth response 1; EMT, epithelial-to-mesenchymal transition; FGFR, fibroblast growth factor receptor; HNC, head and neck cancer; IHC, immunohistochemistry/immunohistochemical staining; IL-8, interleukin-8; IR, ionizing radiation; mAb, monoclonal antibody; MAPK, mutagen-activated protein kinase; MET, mesenchymal-to-epithelial transition receptor; miR, micro-RNA; MMP, matrix metalloproteinase; PDGF, platelet-derived growth factor; PI3K, phosphatidylinositol-3 kinase; RPTP-β, receptor-type protein-tyrosine phosphatase β; RTK/TK, receptor tyrosine kinase/tyrosine kinase; SF/HGF, scatter-factor/hepatocyte growth factor; SNB, sentinel (lymph) node biopsy; ST-14, suppressor of tumorigenicity-14/matriptase; STAT, signal transducer and activator of transcription; TKI, tyrosine kinase inhibitor; VEGF(R), vascular endothelium growth factor (receptor). ☆ Conflict of interest statement: There are no conflicts of interest to be disclosed. ☆☆ Financial support: This manuscript was supported by the Swiss National Science Foundation (to Y.Z.), by the Novartis Stiftung (to Y.Z.) and by the Werner und Hedy Berger-Janser Stiftung (to M.M.). ⁎ Corresponding authors at: Department of Clinical Research, Radiation Oncology, MEM-E815, Murtenstrasse 35, 3010 Bern, Switzerland. Tel.: +41 31 6322543; fax: +41 31 6323297. E-mail addresses: [email protected] (L. Nisa), [email protected] (M. Medová). 1 Equal contribution.

http://dx.doi.org/10.1016/j.pharmthera.2014.04.005 0163-7258/© 2014 Published by Elsevier Inc.

Please cite this article as: Nisa, L., et al., Biological, diagnostic and therapeutic relevance of the MET receptor signaling in head and neck cancer, Pharmacology & Therapeutics (2014), http://dx.doi.org/10.1016/j.pharmthera.2014.04.005

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2.1. Molecular structure and signaling

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MET is the high-affinity RTK for scatter-factor/hepatocyte growth factor (SF/HGF), its only known ligand (Bottaro et al., 1991; Goetsch, Caussanel, & Corvaia, 2013). MET is encoded by the MET protooncogene, which is located in the human 7q13 locus. MET is transcribed as a 6641 bp mRNA, which translates into a single 1390 amino-acid MET precursor protein (Giordano et al., 1989). This precursor is cleaved to yield the mature receptor form, which is composed of the disulfide bound α- and β-subunits. The extracellular α-subunit is highly glycosylated and contains the ligand-binding domain (SEMA domain), which shares homology with members of the semaphorin superfamily of signaling proteins. The β-subunit encompasses the juxtamembrane domain and the catalytically-active tyrosine kinase (TK) domain (Birchmeier, Birchmeier, Gherardi, & Vande Woude, 2003). Binding of SF/HGF triggers receptor dimerization and transphosphorylation of tyrosine residues 1234 and 1235, as well as activation of tyrosine residues 1349 and 1356 within the multidocking site at the C-terminus tail of the receptor (Birchmeier et al., 2003; Giordano et al., 1989). Activation of downstream signaling effectors primarily takes place through the protein adapters growth factor receptor bound protein 2 (Grb2) and Grb2-associated binder 1 (Gab1), which consequently recruit MET targets through interaction with Src-homology-2 (SH2) and phosphotyrosine-binding (PTB) domains (Birchmeier et al., 2003). MET activates several signaling pathways, which are also common to other RTKs (Fig. 1), primarily the mutagen-activated protein kinase (MAPK), the phosphatidylinositol-3 kinase (PI3K)-AKT, and the Januskinase/signal transducer and activator of transcription 3/5 (JAKSTAT3/5) pathways (Liu, Newton, & Scherle, 2010). Although multiple studies over the last two decades have identified numerous signaling components that constitute the very extensive MET signaling network, novel approaches such as post-translational modifications proteomics continue to identify new players which participate in MET-dependent signal transduction (Woodard et al., 2013). There are two main mechanisms to terminate MET signaling. The first one consists of internalization of the receptor, with two potential outcomes: a) immediate ubiquitinization with subsequent proteasomal degradation mediated by the Cbl ubiquitin-ligase; b) maintenance of an active signaling within early endosomes, a relevant mechanism for nuclear translocation of STAT-3 and feedback activation of the MAPK pathway (Jeffers, Taylor, Weidner, Omura, & Vande Woude, 1997; Peschard et al., 2001; Scita & Di Fiore, 2010; Trusolino, Bertotti, & Comoglio, 2010). The second regulatory mechanism is associated with activation of cellular phosphatases. MET regulatory phosphatases include protein-tyrosine phosphatase 1B, protein phosphatase 2A, T-cell phosphatase, LAR protein-tyrosine phosphatase, and density enhanced protein-tyrosine phosphatase-1 (Hashigasako, Machide,

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Head and neck cancer (HNC) is the 6th most common type of cancer worldwide, with over 90% of cases arising in the mucosa of the oral cavity, the oropharynx, the larynx and the hypopharynx. Other less common locations include the nasal cavities and paranasal sinuses, the nasopharynx, the salivary glands, and the skin of the head and neck region. From a histopathological perspective, more than 90% of all cancers in the head and neck region are squamous cell carcinomas (Forastiere, Koch, Trotti, & Sidransky, 2001). HNC has a higher incidence in men than in women, and often develops during the 5th and 6th decades of life. The main risk factors are partly dependent on the primary tumor site and include tobacco and alcohol abuse for the oral cavity, the oropharynx, the larynx, and the hypopharynx; human papillomavirus infection for oropharyngeal carcinomas; and Epstein–Barr virus infection for the nasopharynx (Gillison et al., 2008; Hashibe et al., 2009; Sankaranarayanan, Masuyer, Swaminathan, Ferlay, & Whelan, 1998). Primary tumors arise either as premalignant lesions, such as dysplastic lesions of the oral cavity (Partridge, Emilion, Pateromichelakis, Phillips, & Langdon, 1997) or inverted papillomas of the nasal cavity and paranasal sinuses (Mendenhall et al., 2007), or as carcinomas in situ (Kowalski & Carvalho, 2000), with subsequent local infiltration and early spread to the retropharyngeal and neck lymph nodes (Leemans, Tiwari, Nauta, van der Waal, & Snow, 1993). Advanced HNC may give rise to distant metastases, mainly to the lungs and mediastinum, the liver, and the bones (Ferlito, Shaha, Silver, Rinaldo, & Mondin, 2001). Due to their location, progression of these primary tumors can impair essential functions such as breathing and swallowing, and important features like speech and cosmesis. Furthermore, the effects that the classical treatment options for HNC inflict on the vital structures of the head and neck region cannot be overlooked. Surgical resection can indeed lead to severe impairment of the functions mentioned above. Radiotherapy and concomitant chemotherapy carry substantial skin and mucosal toxicity, and commonly lead to mucosal dryness of the oral cavity and the pharynx. More severe adverse effects of radiation include muscular and/or nervous dysfunction, soft-tissue fibrosis, osteoradionecrosis, and chondroradionecrosis. Collectively, such adverse effects can be life-lasting, making of HNC a disease with an extraordinary burden on patients' quality of life (Argiris, Karamouzis, Raben, & Ferris, 2008; Cognetti, Weber, & Lai, 2008; Gleich et al., 2003; Machtay et al., 2008). Despite moderate improvements in loco-regional control rates, resulting from implementation of multimodal therapy approaches (such as combining surgery and chemoradiation), recurrences and distant metastases still remain devastating forms of disease, often without sufficient/effective treatment options (Argiris et al., 2008; Brockstein, 2011). Indeed, recurrent loco-regional disease or distant metastases after definitive therapy usually have a dismal prognosis since most of the patients may be offered only palliative treatment. Furthermore, even cases in which loco-regional salvage therapy (i.e., surgery and/or re-irradiation) is attempted, do not usually demonstrate a significantly improved prognosis (Specenier & Vermorken, 2008; H. K. Tan et al., 2010; Vermorken & Specenier, 2010). HNC display substantial variety in terms of pathogenesis, progression, and treatment responses, most probably as a consequence of the complex and heterogeneous genetic and epigenetic background of these malignancies (Leemans, Braakhuis, & Brakenhoff, 2011). Increasing research efforts made in order to elucidate the molecular mechanisms of invasiveness, spread and treatment failure, have identified receptors tyrosine kinase (RTKs) as central drivers of oncogenesis in a very broad spectrum of tumors, including HNC (Elferink & Resto, 2011). As such, RTKs have gained substantial interest as therapeutic targets in clinical oncology (Elferink & Resto, 2011; Leemans et al., 2011; Molinolo et al., 2009). The idea of targeting RTKs is that, in

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contrast with the widely used cytotoxic drugs that are rather unspecific, critical processes which are essential and specific for disease progression would be impaired. With respect to HNC, cetuximab, a humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), has been introduced in clinical practice after successful completion of phase III trials (Bonner et al., 2006). Besides EGFR, the mesenchymal-to-epithelial transition (MET) receptor is continuing to gain focus as a molecular target and as a relevant biomarker in HNC. The aim of this review is to summarize currently established evidence and ongoing research concerning the biological, diagnostic, and therapeutic relevance of MET in HNC.

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Please cite this article as: Nisa, L., et al., Biological, diagnostic and therapeutic relevance of the MET receptor signaling in head and neck cancer, Pharmacology & Therapeutics (2014), http://dx.doi.org/10.1016/j.pharmthera.2014.04.005

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Fig. 1. Summary representation of SF/HGF-MET signaling in cancer cells, and its main biological effects. Upon SF/HGF-MET binding, the tyrosine kinase domain of MET triggers a series of phosphorylations which result in activation of several major cell signaling pathways, promoting survival and proliferation, as well as enhanced motility and invasive capacity. Furthermore, MET activates the membrane pool of β-catenin, regulates and is regulated by several EMT-related miRs. Secretion of pro-angiogenic cytokines leads to recruitment of endothelial cells and formation of new blood vessels to sustain tumor growth.

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Table 1 Mechanisms of SF/HGF-MET aberrant activation in HNC.

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Nakamura, & Matsumoto, 2004; Machide, Hashigasako, Matsumoto, & Nakamura, 2006; Palka, Park, & Tonks, 2003; Sangwan et al., 2008; Sangwan et al., 2011). With respect to HNC, receptor-type protein-tyrosine phosphatase β (RPTP-β) has been reported to be downregulated in invasive specimens of HNC when compared with matched samples of normal mucosa (Y. Xu et al., 2012). The same

t1:3

Reference

t1:4

T. Y. Seiwert et al. (2009) MET overexpression MET mutations

t1:5 t1:6

Knowles et al. (2009) t1:7 t1:8 t1:9 t1:10

Morello et al. (2001) Ghadjar et al. (2009) Di Renzo et al. (2000) Ach et al. (2013)

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Findings

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holds true in cell lines derived from metastatic tissues, which show lower levels of RPTP-β in comparison with the matched cell lines derived from primary tumors. Furthermore, while knockdown of RPTP-β results in sustained activation of the MAPK pathway, restoration of its activity in cell lines derived from metastatic tissue decreases MET phosphorylation, downstream signaling, and invasiveness (Y. Xu et al., 2012).

H. Xu et al. (2011) Stabile et al. (2013) Y. Xu et al. (2012) Hara et al. (2006)

In 16/20 cell lines and 84/97 HNC tissues; phosphorylated MET overexpressed in 57/86 tissues. Mutation found in 1/20 cell lines (SEMA domain), and 9/23 tissues (2 in the SEMA domain, 5 in the juxtamembrane domain, and 2 in the tyrosine kinase domain) Gene amplification Increased gene copy number in 3/20 cell lines, and 18/23 tissues (N10 copies in 3/18, 4–10 copies in 15/18) MET overexpression Overexpression of MET in cell lines and tissues. Overexpression of SF/HGF in the stoma compartment Paracrine activation of all tissues. Only paracrine activation reported as a potential oncogenic mechanism. MET overexpression Overexpression only. No mutations found in 12 oral cancer tissue samples. MET mutations Y1235D activating point mutation in primary advanced HNC found in 21/152 patients; strong correlation with the development of distant metastases after definitive therapy. MET mutations Clonal expansion of Y1235D and Y1230C in metastatic lymph nodes. Several genetic lesions 266 salivary gland carcinomas. Lesions: low polysomy (42/266), high polysomy (27/266), amplification (2/266), and deletion (18/266). MET–EGFR crosstalk Ligand-independent activation of MET by EGFR; MET activation by Src in the presence of EGFR inhibitors and in absence of SF/HGF. Downregulation of MET-inhibiting cellular Downregulation of the MET-inhibiting phosphatase RPTP-β in cell lines and specimens derived from phosphatases recurrences of metastatic sites. MET transcriptional activation in hypoxia In two cell lines derived from salivary gland carcinomas.

Please cite this article as: Nisa, L., et al., Biological, diagnostic and therapeutic relevance of the MET receptor signaling in head and neck cancer, Pharmacology & Therapeutics (2014), http://dx.doi.org/10.1016/j.pharmthera.2014.04.005

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MET activation occurs in physiological conditions during embryonic development and during postnatal tissue repair/wound healing (Boccaccio & Comoglio, 2006; Comoglio & Boccaccio, 2001; Huh et al., 2004). At the same time, deregulated MET signaling has been extensively linked to oncogenesis in multiple human malignancies, including HNC (De Herdt & Baatenburg de Jong, 2008). Several mechanisms of MET aberrant signaling have been described in HNC (Table 1), including overexpression of the receptor and/or its ligand, and point mutations (Boccaccio & Comoglio, 2006; Maulik et al., 2002). Regarding preclinical observations, cell lines derived from HNC commonly express high levels of MET, but do not secrete detectable levels of SF/HGF (Knowles et al., 2009). In this context, Knowles et al. (2009) and T. Y. Seiwert et al. (2009) showed that treating HNC cell lines with SF/HGF results in increased cell proliferation, survival, resistance to apoptosis, and cell migration. These preclinical findings are further supported by the fact that both MET and SF/HGF are overexpressed, in the epithelial and stoma compartments respectively, in nearly 80% of tissues derived from HNC patients (Aebersold et al., 2001; Kim, Kim, Kahng, & Choi, 2007; T. Y. Seiwert et al., 2009; Knowles et al., 2009) (Table 2). Moreover, elevated serum levels of SF/HGF correlate with pejorative survival in patients with advanced-stage HNC (Druzgal et al., 2005; Kim et al., 2007; Knowles et al., 2009; Le et al., 2012). Collectively, these observations suggest that MET and SF/HGF paracrine signaling is relevant in HNC pathogenesis and progression (Table 1). MET overexpression is indeed a common feature in solid cancers and can occur as a result of gene amplification (Organ & Tsao, 2011). With respect to MET amplification, T. Y. Seiwert et al. (2009) reported increased MET gene copy number (N4 copies) in 18 out of 23 samples of human HNC. This finding is potentially relevant not only for HNC pathogenesis, but also for treatment responses, since MET amplification, among other mechanisms such as EGFR mutations, has been shown to account for resistance to EGFR inhibitors in lung carcinoma through heterodimerization of MET with members of the ERBB family (Engelman et al., 2007; Sequist & Lynch, 2008). MET mutations established the role of the receptor as an oncogenic driver first in hereditary papillary renal carcinomas (Schmidt et al., 1997), and have since then been reported in several other types of cancer including gastric carcinomas (Lee et al., 2000) and childhood hepatocellular carcinomas (Park et al., 1999). Importantly, a several mutations of the MET receptor were initially described in HNC (Fig. 2) (Ma et al., 2003; Ma et al., 2008; T. Y. Seiwert et al., 2009). Activating point mutations can lead to constitutive activation and determine differential sensitivities to MET inhibitors (Berthou et al., 2004; Zimmer et al., 2010). Most of the mutations displayed in Fig. 2 have also been described in other types of cancer, with different biological consequences and clinical impact. Unfortunately, information is most often derived from tumor entities and preclinical models other than HNC. For instance, the SEMA domain germ-line mutation N375S has been reported in the SCC-25 cell line derived from a human oral carcinoma (T. Y. Seiwert et al., 2009). However, its biologic characterization has been done with lung cancer models. In these studies, the mutation was shown to confer resistance to the MET inhibitor SU11274 (Shieh et al., 2013) and decreased receptor affinity for SF/HGF (Krishnaswamy et al., 2009), without having any prognostic impact in a cohort of patients with lung carcinoma (Shieh et al., 2013). Conversely, the SEMA domain mutation E168D described in patient-derived specimens (T. Y. Seiwert et al., 2009), conferred more susceptibility to MET inhibitors and higher affinity to SF/HGF in preclinical lung cancer models (Krishnaswamy et al., 2009). Concerning mutations of the juxtamembrane domain, mutations such as T1010I and R988C have been equally described in HNC clinical specimens (T. Y. Seiwert et al., 2009), and have been reported to confer

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2.3. Mesenchymal-to-epithelial transition regulation of invasiveness and 275 epithelial–mesenchymal transition in head and neck cancer 276

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mild to moderate IL-3 growth independence in lung small-cell carcinoma cell lines (Ma et al., 2003) as well as increased tumorigenic capacity when expressed in engrafted NIH3T3 cells (Lee et al., 2000). Interestingly, in a recent study Voortman et al. (2013) did not find any functional significance of the T1010I mutation in cell lines and samples of smallcell and neuroendocrine lung carcinomas. Mutations involving the tyrosine kinase domain may confer the receptor with constitutive enzymatic activity. The activating point mutations Y1235D and Y1230C, when present in HNC, are both more highly expressed in metastatic lymph nodes than in the primary tumors of the same patients, suggesting a clonal expansion driven by mutated MET variants as a mechanism of metastatic spread to lymph nodes (Di Renzo et al., 2000). Moreover, Ghadjar et al. (2009) assessed the impact of the Y1235D activating point mutation in a cohort of 152 patients with advanced HNC, and reported that the presence of this mutation is a genetic risk factor for development of distant metastases after completion of definitive therapy. These two studies emphasize the need for further evaluation of the relevance of MET mutations in HNC in well-defined cohorts (i.e., according to anatomical subsites, tumoral stage, and treatments received), as well as the potential use of MET mutations as a marker of stratification for prognosis and treatment responses.

Local, regional, and distant spread of a malignant tumor is a complex multistep process that requires cancer cells to become motile, able to digest and breach the extracellular matrix (ECM), and able to survive in potentially new ‘hostile’ environments. When exposed to certain stimuli, epithelial cells can engage in a morphogenic program referred to as epithelial–mesenchymal transition (EMT), which implies radical changes in gene expression accompanied by subsequent alterations of the original cellular phenotype. At the end of the process, the resulting reprogrammed cell will have lost its initial epithelial features, such as polarity and cell–ell adhesions, eventually acquiring invasive mesenchymal-like characteristics (Boccaccio & Comoglio, 2006; Comoglio & Boccaccio, 2001; De Herdt & Baatenburg de Jong, 2008; Kalluri & Weinberg, 2009). With respect to ECM remodeling, SF/HGF-MET signaling regulates expression and secretion of matrix metalloproteinases (MMPs)-1, -3, and 9, as well as urokinase-type plasminogen activator in hypopharyngeal and oral cancer cells (Hanzawa et al., 2000; Lim et al., 2008). These proteolytic enzymes allow malignant cells to disengage from their highly-organized environment. Once malignant cells detach from their original surrounding ECM, SF/HGF has been shown to further facilitate cellular dissemination via the suppression of anoikis (K. Tan, Goldstein, Crowe, & Yang, 2013). This “protective” mechanism is independent of the NF-kB pathway, which has been implicated in cellular resistance to tumor necrosis factor (TNF)-mediated apoptosis in HNC cells (Zeng et al., 2002).

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2.3.1. Molecular events in relation with epithelial-to-mesenchymal transition following mesenchymal-to-epithelial transition activation Downregulation of E-cadherin and enrichment in mesenchymal proteins such as N-cadherin and vimentin are molecular hallmark features of EMT (Kalluri & Weinberg, 2009). Downregulation of Ecadherin is closely linked with tumoral progression, and its decreased expression in primary tumors correlates with the development of regional lymph node metastases, degree of differentiation, and poor survival in HNC (Andrews, Jones, Helliwell, & Kinsella, 1997; Kurtz, Hoffman, Zimmerman, & Robinson, 2006; Schipper et al., 1991). SF/ HGF-MET signaling modulates the expression and distribution of Ecadherin, leading to its downregulation in several subtypes of HNC (Kim, Kim, Kahng, & Choi, 2007; Murai et al., 2004; Xie et al., 2010). Mechanistically, E-cadherin is associated with intracellular catenins, primarily with β-catenin, which is not only an important structural

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Oral cavity

Y. S. Chen et al. (2004)

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Endo et al. (2006) Lim et al. (2012)

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Lo Muzio et al. (2004) Kim et al. (2010)

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Lo Muzio et al. (2006) Kim et al. (2006)

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Yucel et al. (2004)

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Nasopharynx

Sawatsubashi et al. (1998) Xie et al. (2010)

Oropharynx

Qian et al. (2002) Aebersold et al. (2001)

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Knowles et al. (2009) Choe et al. (2012)

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No Advanced N-stage (p = 0.035)

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Advanced T-stage (p = 0.01) Not assessed Advanced N-stage (p = 0.003) Advanced T-stage (p = 0.04) No Advanced N-stage Decreased overall survival (p (p = 0.002) Advanced T-stage (p = 0.03) Decreased overall survival (p Advanced N-stage Decreased overall survival (p (p = 0.005) No Decreased overall survival (p Advanced N-stage No (p = 0.006) Advanced T-stageb No Advanced N-stageb Advanced N-stage No (p = 0.032) Advanced N-stage No (p b 0.001)

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= 0.036)

SF/HGF expression had no impact on survival or clinical stage – E-cadherin cellular location has an impact on prognosis –

SF/HGF and E-cadherin expression correlate with advanced N-stage; E-cadherin cellular location has an impact on prognosis – MET expression inversely correlated with response to radiotherapy – Subsite distribution: oral (16%), oropharyngeal (21%), laryngeal (35%), hypopharyngeal (4%), and nasopharyngeal-nasosinusal (24%)

The method of detection used in all the studies was immunohistochemistry. p-values were not provided in this study.

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protein of the cytoskeleton, but also a major cytoplasmic component of the Wnt-signaling pathway (Kikuchi, Yamamoto, & Sato, 2009). Experimental observations have shown that MET can induce nuclear translocation of β-catenin in a Wnt-independent manner, by phosphorylating the membrane-associated pool of β-catenin instead of the cytoplasmic pool activated by Wnt ligands (Hiscox & Jiang, 1999; Monga et al., 2002). Following nuclear translocation, β-catenin interacts with transcription factors of the TCF/LEF family, co-regulating the expression of several genes that confer cells with mesenchymal features (Brantjes, Barker, van Es, & Clevers, 2002). Interestingly, MET is itself a transcriptional target of β-catenin (Rasola et al., 2007). In cell lines derived from hypopharyngeal carcinomas, stimulation with SF/HGF results in transcriptional downregulation and cellular redistribution of E-cadherin in a dose-dependent manner (Kim, Kim, Kahng, & Choi, 2007). Indeed, upon SF/HGF stimulation, the predominantly membrane form of E-cadherin accumulates in the cytoplasm, where it is no longer functional. In clinical specimens, E-cadherin staining is mainly membranous in normal mucosa, while in malignant cells it is non-membranous, with a parallel and correlated overexpression of SF/HGF in the same tumor regions (Kim, Kim, Kahng, & Choi, 2007). In line with these findings, treating nasopharyngeal carcinoma cell lines with SF/HGF also results in decreased levels and redistribution of E-cadherin. Similarly, in clinical specimens the areas displaying predominantly cytoplasmic E-cadherin staining also display high SF/HGF levels (Xie et al., 2010). Univariate survival analysis in a cohort of 135 patients with nasopharyngeal carcinoma showed that high SF/HGF expression and non-membranous E-cadherin staining were associated with poor survival. In the multivariate analysis non-membranous E-cadherin, along with the presence of lymph node metastases, were the only predictors of decreased survival (Xie et al., 2010).

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= 0.03) = 0.003)

MET expression higher in malignant and premalignant lesions (compared to normal mucosa) – –

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= 0.018)

Decreased overall survival (p b 0.001) Decreased disease-free survival (p = 0.003) Decreased overall survival (p b 0.001) Not assessed No

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Impact on survival

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Table 2 MET overexpression and its correlation with clinico-pathological features in HNCa.

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Similar findings have been described also in cell lines as well as in 348 tissues of patients with oral carcinomas (Murai et al., 2004; Uchida 349 et al., 2001). 350

2.3.2. Micro-ribonucleic acids participating in mesenchymal-to-epithelial transition-induced invasiveness of head and neck cancer Micro-RNAs (miRs) are small non-coding 19–25 nucleotide RNAs that exert post-transcriptional regulation of gene expression. Therefore, miRs are considered to orchestrate cellular processes such as cell proliferation, differentiation, metabolism, and apoptosis. Aberrant expression of miRs has been linked with pathological processes including oncogenesis (Kloosterman & Plasterk, 2006). In this respect, SF/HGF-MET signaling regulates and is in turn regulated by several miRs that play an essential role in invasiveness and EMT. Specifically, concerning MET signaling in HNC, the information available is still limited but illustrative. For instance, SF/HGF stimulation results in the downregulation of miR-200c, which in turn results in ZEB1 upregulation. ZEB1 is a major transcriptional repressor of E-cadherin (Susuki et al., 2011). MET activation also induces downregulation of miR-27b, leading to increased levels of suppressor of tumorigenicity-14/matriptase (ST-14) on the cell surface. ST-14 participates in the digestion of the ECM and also in the cleavage of the inactive, matrix-bound SF/HGF (Susuki et al., 2011). As to miRs involved in the regulation of MET expression, miR34c downregulates MET and its overexpression inhibits proliferation in laryngeal carcinoma cell lines while abrogating their invasive phenotype. Moreover, miR-34c is significantly downregulated in laryngeal carcinoma tissues as compared to adjacent normal mucosa. Therefore, downregulation of miR-34c in laryngeal cancer with subsequent upregulation of MET could explain at least partially the aggressive phenotype seen in cell lines and tissues with miR-34c decreased expression (Cai et al., 2010).

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Fig. 2. Schematic representation of the MET receptor and the mutations reported in HNC. MET mutations in HNC have been identified primarily within the TK domain and usually associate with increased tyrosine kinase activity in preclinical models. The biologic impact of the mutations in the juxtamembrane region and in the SEMA domain of the extracellular portion has not yet been characterized in HNC.

2.5. Mesenchymal-to-epithelial transition regulation of angiogenesis in head and neck cancer

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In order to sustain tumoral growth beyond a critical volume, tumors must be able to induce the formation of new blood vessels (neoangiogenesis). Vascular endothelial growth factors (VEGFs) and their cognate receptors (VEGFRs) play a prominent role in this process, but also several other RTKs such as fibroblast growth factor receptors (FGFRs), platelet-derived growth factor receptors (PDGFRs), and EGFR have been identified to contribute in the process of neoangiogenesis in HNC (T. Y. Seiwert & Cohen, 2008). SF/HGF-MET signaling has been shown to have a dual pro-angiogenic effect in tumorigenesis. On one hand, MET activation induces expression and secretion of several coagulation factors and important pro-angiogenic growth factors and cytokines such as VEGF, PDGF, and interleukin-8 (IL-8) (Worden et al.,

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HNC tumors largely consist of heterogeneous populations of cells including benign and malignant epithelial cells, endothelial cells, cancer-associated as well as normal fibroblasts, and immune cells (C. Chen, Zimmermann, Tinhofer, Kaufmann, & Albers, 2013). Cancer stem-like cell cells (CSCs) represent a subpopulation of malignant cells functionally characterized by multipotency, tumor initiating, and self-renewal capacities. CSCs are currently considered to play a potentially relevant role in disease progression and treatment resistance in HNC (C. Chen et al., 2013; Prince et al., 2007; Wollenberg, 2011). Even though CSCs do not have a definite signature, aldehyde dehydrogenase (ALDH), CD44, CD133, Nanog, Notch, Snail, Twist, vimentin, and podoplanin are proteins widely used as CSCs markers in HNC (C. Chen et al., 2013; Z. Zhang, Filho, & Nor, 2012). Additionally, MET has equally been identified as a putative marker for CSCs in HNC. Indeed, MET+ cells isolated from patient-derived primary tumors are more tumorigenic than MET−/CD44+ and MET−/CD44− cells, the latter of which fail to produce any tumors in nude mice. MET+/CD44+, along with ALDH-high cells, have the highest tumorigenic capacity and increased clonogenic survival when exposed to cisplatin (Sun & Wang, 2011). Further in the sense of cisplatin resistance, xenografts established in nude mice showed an accumulation of MET + cells following prolonged treatment with cisplatin (Sun & Wang, 2011). Importantly, after irradiation of HNC tissues, the population of ALDH-high cells is enriched and displays features of radioresistance (Y. C. Chen et al., 2009; Chinn, Darr, Peters, & Prince, 2012). The mechanisms of CSCs radio- and/or chemo-resistance are currently under-characterized, and the ability to target CSCs through inhibition of the SF/HGF-MET signaling pathway is an important research question to be addressed in HNC (Albers et al., 2012).

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2005). On the other hand, MET signaling has been reported to downregulate angiogenesis antagonists such as thrombospondin-1, an inducer of apoptosis in endothelial cells (Y. W. Zhang, Su, Volpert, & Vande Woude, 2003). Specifically concerning relevant molecular mechanisms of angiogenesis in HNC, MET activation by SF/HGF leads to a rapid and transient induction of the early growth response 1(Egr-1) transcription factor, which is necessary for expression and secretion of PDGF and VEGF by tumor cells (Worden et al., 2005). In an Egr-1-independent manner, MET also leads to secretion of IL-8 (Worden et al., 2005). Single inhibition of either PI3K or MAPK pathways leads to partial reduction of SF/ HGF-induced secretion of IL-8 and VEGF, and dual blockade of these pathways completely abrogates expression and secretion of proangiogenic molecules (Dong et al., 2001). Inhibition of the SF/HGFMET pathway using tyrosine kinase inhibitors (TKIs) also leads to a significant reduction of angiogenesis in cell line-derived xenografts (T. Y. Seiwert et al., 2009). Importantly, crosstalk between MET and VEGFR2 results in synergistic activation of downstream effectors (MAPK, PI3K-AKT, focal adhesion kinase), which ultimately leads to increased proliferation of endothelial cells in addition to the aforementioned secretion of pro-angiogenic growth factors and cytokines (Sulpice et al., 2009). A recent phase II trial including HNC patients employing the antiMET/anti-VEGFR-2 multikinase inhibitor foretinib was discontinued as, even though 50% of the patients achieved disease stabilization, none experienced tumoral remission (T. Seiwert et al., 2013). This cohort included either patients that were not suitable for primary curative treatment or patients that did not respond to standard therapy and for whom salvage was not an option. It is important to note that single therapeutic agents have classically shown little or no activity at all in HNC, and since the role of MET inhibitors in HNC treatment is yet to be fully characterized in clinical trials, the results of this study have to be considered as preliminary observations.

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Collectively, these observations suggest potential prominent roles for the interplay between MET-associated upstream and downstream miRs in the invasive behavior of HNC.

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3. Diagnostic relevance of mesenchymal-to-epithelial transition in 460 head and neck cancer 461 3.1. Mesenchymal-to-epithelial transition overexpression and its correla- 462 tion with clinico-pathological features in head and neck cancer 463 Given the emerging role of the SF/HGF-MET axis in HNC, several studies have evaluated the correlation between MET expression and several clinical and pathological features in HNC. Based on immunohistochemical staining (IHC),MET overexpression has been reported in neoplastic tissue compared to matched normal epithelium of the same anatomic regions in oral (Y. S. Chen et al., 2004; Choe, Yun, Nam, & Kim, 2012; Endo, Shirai, Furukawa, & Yoshizaki, 2006; Kim et al., 2010; Lim et al., 2012; Lo Muzio et al., 2006; Lo Muzio et al., 2004; Morello et al., 2001), nasopharyngeal (Qian et al., 2002), oropharyngeal (Aebersold et al., 2001), laryngeal (Sawatsubashi, Sasatomi, Mizokami, Tokunaga, & Shin, 1998; Yucel, Sungur, & Kaya, 2004), and hypopharyngeal carcinomas (Kim et al., 2006). Furthermore, in addition to MET overexpression in HNC tissues,

Please cite this article as: Nisa, L., et al., Biological, diagnostic and therapeutic relevance of the MET receptor signaling in head and neck cancer, Pharmacology & Therapeutics (2014), http://dx.doi.org/10.1016/j.pharmthera.2014.04.005

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3.2.2. Mesenchymal-to-epithelial transition as a biomarker for the diagnostic of distant metastases Distant metastases have a major impact on prognosis and survival of HNC patients. About 5% of all patients present with distant metastases at diagnosis, and 10% of all patients will develop distant metastases after completion of therapy (Leon, Quer, Orus, del Prado Venegas, & Lopez, 2000). The treatment options are poorly efficient in such scenarios, with palliative chemotherapy, and, when possible, radiotherapy/ surgery as the mainstay of disease management (de Bree, Deurloo, Snow, & Leemans, 2000). Only a very limited number of studies have addressed the correlation between MET expression and distant metastases (Aebersold et al., 2001; Kim, Kim, Kahng, & Choi, 2007; Kim et al., 2006; Kim et al., 2010), generally indicating a low correlation between these two variables. Using a different approach, a prospective study from our own group that included 152 patients with advanced-stage HNC showed that the presence of the Y1235D activating point mutation within the MET TK domain was an independent genetic risk factor for development of distant metastases (HR: 2.49; CI: 1.06–5.82, p = 0.036 on the multivariate analysis) (Ghadjar et al., 2009). Although this study is to the best of our knowledge the only one addressing this important question, its results provide promising ground for further studies including additional MET mutations to assess their significance in the context of metastatic disease. It is equally reasonable to speculate that MET mutations may have the potential to delineate subsets of patients that may preferentially benefit from anti-MET targeted therapies.

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3.2.1. Mesenchymal-to-epithelial transition as a biomarker for the diagnostic of lymph node metastases HNC is characterized by early spread to regional lymph nodes (retropharyngeal and neck), and metastatic involvement of lymph nodes is considered the single most important prognostic factor identified in HNC until present (Argiris et al., 2008; Ghadjar et al., 2010). Consequently, accurate staging of lymph node involvement is essential to determine both disease extension and subsequent need for appropriate treatment strategies (Ghadjar et al., 2010). Histopathological examination of operative samples complemented with different IHC protocols is the current gold-standard technique used to diagnose lymph node metastases. Obviously, these methods have limited sensitivity and specificity. Thus micrometastases (b2 mm) represent a significant diagnostic challenge (Ferlito, Partridge, Brennan, & Hamakawa, 2001), with a major clinical impact as the detection of micrometastases may trigger the indication for adjuvant chemoradiation and may also determine the appropriate radiation volume (Vorwerk & Hess, 2011). Given the frequent association between high MET expression in primary tumors with lymph node metastases and the fact that MET expression is more abundant in metastatic lymph nodes than in matched primary tumors, detection of MET in metastatic lymph nodes is a potentially interesting adjuvant diagnostic method (Galeazzi et al., 1997).

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A study using MET-specific real-time quantitative polymerase chain reaction to assess lymph node status in 20 patients with HNC reported that MET-based staging of lymph nodes was more accurate than other methods including routine and in-depth histopathological procedures (Cortesina et al., 2000). Indeed, MET-specific RT-PCR allowed upgrading N-stage in several cases, especially in four patients initially classified as pN0 (absence of lymph node metastases), which turned out to be all positive with MET-based staging. MET RT-PCR was also superior to cytokeratin staining and allowed upgrading the pN stage in five cases out of 20 (25%) (Cortesina et al., 2000). In order to fully establish the diagnostic relevance of MET as a biomarker of lymph node metastases in HNC, further studies are needed. An interesting aspect to investigate in future studies is the detection of MET in sentinel lymph node biopsy (SNB) specimens, a minimallyinvasive procedure currently validated in the staging of neck lymph node metastases of oral and oropharyngeal carcinomas (Broglie, Haerle, Huber, Haile, & Stoeckli, 2013). Indeed, techniques of molecular detection based on several markers combined with SNB have shown promise in numerous preliminary studies in HNC (Ferris et al., 2011; Huber et al., 2011; Trivedi, Mattos, Gooding, Godfrey, & Ferris, 2013).

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substantial differences have been reported with respect to the receptor distribution within the tumor itself, as the highest expression levels have been detected particularly at the invasive front, with the cells at this location exhibiting higher levels of MET nuclear localization (Brusevold, Soland, Khuu, Christoffersen, & Bryne, 2010). The biologic significance of this observation has yet to be further investigated. Another indication for the role that MET aberrant expression may have in the progression of HNC, or at least in particular subtypes, are the differences of both MET and SF/HGF levels of expression between premalignant versus invasive lesions as has been reported in oral carcinomas (Y. S. Chen et al., 2004; Endo et al., 2006). The correlation between MET expression and disease stage, particularly that of the primary tumor (T-stage) and the corresponding lymph nodes (N-stage), has been assessed in several studies. Table 2 summarizes the main findings of relevant studies, most of which deal with a single subsite of the head and neck region. Concerning the oral cavity, a significant association between MET overexpression and lymph node metastases (Y. S. Chen et al., 2004; Endo et al., 2006; Kim et al., 2010; Lim et al., 2012) is often found, while the association with advanced T-stage is less consistent (Y. S. Chen et al., 2004; Endo et al., 2006; Lo Muzio et al., 2004) (Table 2). Such differences are most likely due to the fact that the populations of patients assessed were substantially heterogeneous in terms of tumoral stage. Furthermore, inter-observers' differences in evaluation of IHC can equally contribute to the discordant findings mentioned above. MET overexpression has been reported to be systematically associated with advanced Nstage in laryngeal and hypopharyngeal carcinomas (Kim et al., 2006; Sawatsubashi et al., 1998; Yucel et al., 2004), but only one study reported a significant association with advanced T-stage in this subset of HNCs (Yucel et al., 2004) (Table 2). Similarly, in patients with nasopharyngeal cancer, MET overexpression invariably correlates with advanced N-stage, but not T-stage (Qian et al., 2002; Xie et al., 2010) (Table 2). Unfortunately, only one study focused on oropharyngeal cancer, which is one of the most common subtypes of HNC. The authors reported a significant association between MET overexpression and N-stage, but not T-stage (Aebersold et al., 2001) (Table 2). Finally, two studies included patients with different subtypes of HNC and heterogeneous stages, without applying any type of stratification, therefore obtaining variable results (Choe et al., 2012; Knowles et al., 2009).

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3.3. Correlation between mesenchymal-to-epithelial transition expression, 588 treatment response, and survival in patients with head and neck cancer 589 The current number of studies assessing the correlation between MET expression and treatment response and survival is very limited (Table 2). The findings in these studies also demonstrate the same limitations mentioned in chapter 3.1. Furthermore, not all studies shown in Table 2 provide multivariate survival analysis, which constitutes an obvious limitation in result interpretation. In terms of treatment responses, Aebersold et al. (2001) evaluated 97 patients with oropharyngeal cancer and showed that high MET expression is a strongly significant independent risk factor for local tumor recurrence after radiotherapy. Additionally, in a cohort of 138 patients with oropharyngeal cancer, the presence of the Y1253D mutation was associated with decreased control of the primary tumor after radiotherapy, the main treatment strategy for this type of neoplasms (Aebersold et al., 2003). These two studies are the only reports

Please cite this article as: Nisa, L., et al., Biological, diagnostic and therapeutic relevance of the MET receptor signaling in head and neck cancer, Pharmacology & Therapeutics (2014), http://dx.doi.org/10.1016/j.pharmthera.2014.04.005

590 591 592 593 594 595 596 597 598 599 600 601 602 603

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Table 3 summarizes clinical trials of various anti-MET therapeutic approaches, most of which included HNC patients within trial populations constituted by various types of advanced solid tumors. With respect to antibodies neutralizing SF/HGF, rilotumumab and ficlatuzumab have reached phase II clinical trials, and TAK-701 has completed a phase I trial (Blumenschein, Mills, & Gonzalez-Angulo, 2012; Gherardi, Birchmeier, Birchmeier, & Vande Woude, 2012; Giordano, 2009). None of the phase II studies included patients with HNC. Onartuzumab and LY-2875358 are humanized anti-MET antibodies that have reached phase III and II clinical trials, respectively (Blumenschein et al., 2012). Even though none of the most advanced trials included patients with HNC, the phase II trial combining onartuzumab with erlotinib (EGFR inhibitor) showed a benefit in progression-free survival for patients with positive MET IHC (Spigel et al., 2013). The corresponding phase III trial in lung cancer is currently ongoing (trial ID: NCT01456325) (Spigel et al., 2012). As for MET small molecule inhibitors, both MET-specific as well as multikinase TKIs have been evaluated in patients with HNC. Regarding multikinase inhibitors, both treatment responses and toxicity can therefore not be fully attributed to MET inhibition alone, as is the case with inhibitors of other tyrosine kinase targets (van der Kuip, Wohlbold, Oetzel, Schwab, & Aulitzky, 2005). The anti-MET multikinase inhibitor foretinib was tested in a phase II trial assessing only HNC patients. This open-label, single-arm trial included 14 patients with recurrent/metastatic HNC, or patients that were otherwise not suitable for primary curative-intent therapy. Seven out of 14 patients reached disease stabilization (2 of these patients for a prolonged period over 12 months), 6 out of 14 underwent certain degree of tumor remission, and the treatment was generally well tolerated, without severe adverse effects (T. Seiwert et al., 2013). Several other MET-specific TKIs such as EMD1214063, EMD1204831 (discontinued), and tivantinib, as well as the multikinase inhibitors crizotinib, cabozantinib, MGCD-265, golvatinib and AMG 208, have been or are being tested in some patients with HNC included in heterogeneous groups of patients with advanced solid tumors, usually in phase I and II trials (Burtness, Bauman, & Galloway, 2013; Gherardi et al., 2012). An ongoing phase II clinical trial is evaluating cetuximab with or without tivantinib in patients with recurrent, metastatic, or non-operable HNC (trial ID: NCT1696955). Tivantinib showed promising results in a phase II trial for hepatocellular carcinoma, especially in the subgroup of patients with high MET expression (Santoro et al., 2013).

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• Impairing ligand–receptor binding using antibodies neutralizing SF/HGF or antibodies that bind MET. • Inhibiting the catalytic activity of the TK domain, usually by the use of tyrosine kinase inhibitors (TKIs). • Inhibiting MET downstream signaling effectors.

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4.2. Targeting mesenchymal-to-epithelial transition receptor in combina- 690 tion with ionizing radiation 691

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Therefore, based on the findings in lung cancer and hepatocellular carcinoma, it is plausible to speculate that stratification according to MET expression in clinical trials including MET inhibitors for HNC will potentially yield more meaningful result interpretation. Additionally, given the experience with EGFR inhibitors in lung cancer, an important question will be correlating MET mutational status and responses to particular inhibitors (Paez et al., 2004). Due to their design, most clinical trials do not allow drawing any specific conclusions on the efficacy of targeted MET inhibition in HNC. The potential clinical use of MET inhibitors in HNC urgently needs further evaluation in more specifically designed clinical trials with larger cohorts. Finally, another option to abrogate SF/HGF-MET signaling is to target or co-target downstream effectors. However, in that respect, much less data are available as to such potential dual inhibition of MET and signaling molecules in comparison with other RTKs and particularly, with EGFR (Burtness et al., 2013). This is an important field of preclinical research, since dual inhibition of EGFR and the PI3K pathway by the TKIs erlotinib and LY294002 respectively, has been shown to result in additive cytotoxic effects, impairment of tumor growth, and increased apoptotic rates in preclinical HNC models (Young et al., 2013). The same holds true when dually targeting MET and the non-receptor TK Src (discussed in more detail in chapter 4.3.2) (Sen, Peng, Saigal, Williams, & Johnson, 2011).

Radiotherapy is, along with surgery, a major treatment modality for HNC. Early stage HNC is usually treated with a single therapeutic modality (surgery or radiotherapy), while advanced HNC require most often combinations of both modalities adding concomitant chemotherapy (Argiris et al., 2008). Radiotherapy (and more generally ionizing radiation (IR)) exerts its cytotoxic activity primarily by inflicting DNA damage via generation of reactive oxygen species (Friedland et al., 2008). For radiotherapy to effectively eradicate tumors, the capacity of tumor cells to overcome DNA damage needs to be surpassed. In this context, the goal of concomitant administration of cytotoxic drugs is to enhance and to sustain the corresponding IR-induced DNA damage. Thus, the biologic rationale underlying inhibition of growth factor receptors along with IR is to achieve radiosensitization by impairing potential RTKs crosstalk with the DNA damage response (DDR) machinery, which could eventually account for effective DNA repair in tumor cells (Medova, Aebersold, & Zimmer, 2013). Several RTKs have been suggested to crosstalk with the DDR following irradiation of tumor cells. In this respect, the first and the most studied RTK is the EGFR, which was shown to interact with DNAdependent protein kinase, a major effectors of non-homologous endjoin repair of DNA double strand breaks (Bandyopadhyay, Mandal, Adam, Mendelsohn, & Kumar, 1998). Moreover, several preclinical studies have shown the ability of various EGFR inhibitors such as cetuximab and vandetanib to radiosensitize HNC cell lines (Gustafson, Frederick, Merz, & Raben, 2008; Holz et al., 2011; Lu, Liang, Lu, & Fan, 2012). The first observations suggesting that MET activation may play important roles in cellular responses to DNA-damaging agents originated from the group of Elliot Rosen over 15 years ago (Fan et al., 1998; Fan et al., 2000). Importantly, these studies demonstrated reduced DNA damage either in the form of single as well as double strand breaks in breast and prostate tumor cells, when cells were treated by SF/HGF prior to exposure to DNA-damaging agents. The same group has also provided evidence for the relevance of the PI3K pathway in mediating MET-dependent protective effects. In this respect, subsequent studies originating from our laboratory suggest that MET inhibition results in DNA damage, in the impairment of DNA double strand breaks repair via homologous recombination, and when combined with IR or radiomimetic drugs, enhances the extent of DNA damage and delays its

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The prominence of the SF/HGF-MET signaling pathway in cancer onset and tumor progression highlights its position as a very promising therapeutic target in HNC (Elferink & Resto, 2011; Ferreira, Lima, & Cohen, 2012; Lau & Chan, 2011; Maroun & Rowlands, 2013; T. Y. Seiwert et al., 2009; Knowles et al., 2009). In clinical practice, several strategies can be used to therapeutically inhibit SF/HGF-MET signaling:

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4. Therapeutic relevance of mesenchymal-to-epithelial transition in head and neck cancer

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evaluating the impact of MET expression/mutations in treatment responses. Further studies in this direction are therefore essential, especially when considering the foreseeable clinical implementation of antiMET targeted therapies in HNC.

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Please cite this article as: Nisa, L., et al., Biological, diagnostic and therapeutic relevance of the MET receptor signaling in head and neck cancer, Pharmacology & Therapeutics (2014), http://dx.doi.org/10.1016/j.pharmthera.2014.04.005

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L. Nisa et al. / Pharmacology & Therapeutics xxx (2014) xxx–xxx t3:1 t3:2 t3:3

Table 3 Main agents targeting MET and/or SF/HGF in clinical trialsa. Type of agent

Agent

Company

Status in clinical trials

Observations

Anti-SF/HGF mAbs

Rilotumumab

Amgen

Phase II in solid tumors

Ficlatuzumab

AVEO

Phase II in solid tumors

TAK-701 Onartuzumab LY-2875358

Millenium Pharmaceutics Genentech Eli Lilly

Phase I in solid tumors Phase III in solid tumors Phase II in solid tumors

Foretinib

Exelixis

Phase II in HNC patients

EMD1214063 EMD1204831 Crizotinib

EMD Serono EMD Serono Pfizer

Phase I in solid tumors Phase I in solid tumors Phase II and III

Tivantinib

ArQule

Phase II in solid tumors (and phase III for non-HNC)

Cabozatinib

Exelixis

MGCD-265

MethylGene

Phase II in solid tumors and phase III in medullary thyroid carcinoma Phase II

Several phase II trials for different types of solid tumors (e.g. glioma, gastric, esophageal, colorectal, prostate, renal, lung), usually in combination with other molecules (e.g. cisplatin, bevacizumab, panitumumab) Tested in combination with gefitinib in Asian patients with non-small-cell lung cancer (phase II) (trial ID: NCT01039948). – – Ongoing phase II trial in patients with MET positive advanced gastric carcinoma (trial ID: NCT01874938), MET positive non-small cell lung carcinoma (trial ID: NCT01900652) Completed phase II trial, without significant benefit as single treatment for recurrent, metastatic, inoperable HNC – Discontinued FDA approved for the treatment of patients with ALK positive metastatic non-small cell lung cancer Phase II trial – cetuximab with or without tivantinib – in patients with recurrent, metastatic, or non-resectable HNC Phase II in hepatocellular carcinoma showed benefit in overall survival in patient with high MET expression; ongoing phase III trial in patients with hepatocellular carcinoma FDA approved for medullary thyroid carcinoma

AMG 208 Golvatinib

Amgen Eisai

Phase II in solid tumors Phase II

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t3:5 t3:6 t3:7

Anti-MET mAbs

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Tyrosine kinase inhibitors

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The references used can be found in the text (chapter 4.1).

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Addition of cytotoxic drugs to radiotherapy is a standard procedure for the treatment of advanced-stage HNC, either in neo-adjuvant, concomitant, and/or adjuvant setting (Majem et al., 2006; Pignon, le Maitre, Maillard, & Bourhis, 2009). The most commonly used agent is cisplatin, followed by 5-fluorouracil. These drugs are rather unspecific and target quickly proliferating cells regardless of their malignant or

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resolution (Ganapathipillai et al., 2008; Medova, Aebersold, & Zimmer, 2012; Medova et al., 2010; Medova et al., 2013). The link between MET and cellular responses to IR in general is far more intricate, as IR has been shown to induce expression and constitutive activation of MET (De Bacco et al., 2011). Furthermore, MET is a hypoxia-inducible gene known to play an important role in the invasive behavior of hypoxic malignant cells and in responses to IR (Pennacchietti et al., 2003). It is worthy to note that the results of currently available studies concerning MET inhibition combined with IR are derived from tumors other than HNC. Furthermore, in most of these studies, cells with MET gene amplification displaying features of oncogene-addiction were used. This poses a serious limitation to extrapolate the link between MET and the DDR in HNC due to two main reasons: 1) unlike in other tumor types (e.g., gastric, lung), MET addiction has not been yet reported in preclinical models of HNC and; 2) recent studies with lung cancer cell lines showed that oncogene-addiction is an important determinant in the link between MET inhibition and the DDR (Bhardwaj et al., 2012). Nonetheless, in view of the aforementioned observations, an essential preclinical and clinical necessity in HNC is to assess the potential of targeting MET along with radiotherapy. In this context, it is however important to point out that no clinical trials evaluating combinations of MET inhibitors and radiotherapy have been established yet with any malignant disorder.

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Phase I completed with multiple types of solid tumors; ongoing phase II focused on lung cancer – Ongoing phase II trial in patients with platinum-resistant metastatic, recurrent, or inoperable HNC: cetuximab with or without golvatinib (trial ID: NCT01332266)

benign origin, resulting in considerable rates of acute and late toxicity (Machtay et al., 2008; Toohill et al., 1987). Since there is a substantial variability in responses to chemotherapy among patients with HNC, an imminent necessity to elucidate the mechanisms of resistance and response to such drugs exists. With respect to MET, HNC cell lines that are sensitive to cisplatin display low MET expression. Similarly, clinical samples from patients that had a complete response to neo-adjuvant chemotherapy exhibit low levels of MET, while only 20% of patients with high MET expression responded completely to chemotherapy (Akervall et al., 2004). Moreover, as aforementioned (in chapter 2.4.), prolonged exposure to cisplatin leads to selection and expansion of MET+ clones in xenografts derived from HNC samples (Sun & Wang, 2011). Finally, it is important to point out that combined treatment consisting of cisplatin along with MET inhibitors has been reported to result in additive reduction of cell proliferation and increased apoptosis (T. Y. Seiwert et al., 2009). Further translational studies and design of clinical trials to elucidate the potential for therapies combining cisplatin and MET inhibitors to improve loco-regional control and eventually reduce toxicity/IR-doses in HNC are needed.

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4.3.1. Role of mesenchymal-to-epithelial transition receptor in resistance to molecular targeted therapies Molecular targeted therapy for HNC in clinical practice consists currently only of EGFR inhibitors. The most prominent agent targeting EGFR in HNC is the fully-humanized mAb cetuximab (Leemans et al., 2011; Milas, Fan, Andratschke, & Ang, 2004; Nicholson, Gee, & Harper, 2001). Cetuximab, when combined with radiotherapy, was shown to improve overall survival in patients with HNC, but no data were provided with respect to loco-regional control in a prospective 5-year followup study (Bonner et al., 2010; Harrington, 2010). The results of antiEGFR targeted therapy have been modest in terms of loco-regional

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Ach, T., Zeitler, K., Schwarz-Furlan, S., Baader, K., Agaimy, A., Rohrmeier, C., et al. (2013). Aberrations of MET are associated with copy number gain of EGFR and loss of PTEN and predict poor outcome in patients with salivary gland cancer. Virchows Arch 462, 65–72. Aebersold, D. M., Kollar, A., Beer, K. T., Laissue, J., Greiner, R. H., & Djonov, V. (2001). Involvement of the hepatocyte growth factor/scatter factor receptor c-met and of Bcl-xL in the resistance of oropharyngeal cancer to ionizing radiation. Int J Cancer 96, 41–54. Aebersold, D. M., Landt, O., Berthou, S., Gruber, G., Beer, K. T., Greiner, R. H., et al. (2003). Prevalence and clinical impact of Met Y1253D-activating point mutation in radiotherapytreated squamous cell cancer of the oropharynx. Oncogene 22, 8519–8523. Akervall, J., Guo, X., Qian, C. N., Schoumans, J., Leeser, B., Kort, E., et al. (2004). Genetic and expression profiles of squamous cell carcinoma of the head and neck correlate with cisplatin sensitivity and resistance in cell lines and patients. Clin Cancer Res 10, 8204–8213. Albers, A. E., Chen, C., Koberle, B., Qian, X., Klussmann, J. P., Wollenberg, B., et al. (2012). Stem cells in squamous head and neck cancer. Crit Rev Oncol Hematol 81, 224–240. Andrews, N. A., Jones, A. S., Helliwell, T. R., & Kinsella, A. R. (1997). Expression of the E-cadherin-catenin cell adhesion complex in primary squamous cell carcinomas of the head and neck and their nodal metastases. Br J Cancer 75, 1474–1480. Argiris, A., Karamouzis, M. V., Raben, D., & Ferris, R. L. (2008). Head and neck cancer. Lancet 371, 1695–1709. Bandyopadhyay, D., Mandal, M., Adam, L., Mendelsohn, J., & Kumar, R. (1998). Physical interaction between epidermal growth factor receptor and DNA-dependent protein kinase in mammalian cells. J Biol Chem 273, 1568–1573. Berthou, S., Aebersold, D. M., Schmidt, L. S., Stroka, D., Heigl, C., Streit, B., et al. (2004). The Met kinase inhibitor SU11274 exhibits a selective inhibition pattern toward different receptor mutated variants. Oncogene 23, 5387–5393. Bhardwaj, V., Zhan, Y., Cortez, M. A., Ang, K. K., Molkentine, D., Munshi, A., et al. (2012). C-Met inhibitor MK-8003 radiosensitizes c-Met-expressing non-small-cell lung cancer cells with radiation-induced c-Met-expression. J Thorac Oncol 7, 1211–1217. Birchmeier, C., Birchmeier, W., Gherardi, E., & Vande Woude, G. F. (2003). Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4, 915–925. Blumenschein, G. R., Jr., Mills, G. B., & Gonzalez-Angulo, A. M. (2012). Targeting the hepatocyte growth factor-cMET axis in cancer therapy. J Clin Oncol 30, 3287–3296. Boccaccio, C., & Comoglio, P. M. (2006). Invasive growth: a MET-driven genetic programme for cancer and stem cells. Nat Rev Cancer 6, 637–645.

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HNC, potentially conferring tumors with increased and sustained growth, invasiveness, reduced apoptosis, survival, and concomitant resistance to anti-cancer treatments. MET expression levels and mutations are potentially relevant biomarkers for lymph node and distant metastases. In view of this, MET has gained an obvious interest both as a molecular target which might serve as a driver of tumorigenesis in HNC as well as an effectors of resistance to both existing and upcoming treatments. Available preclinical data derived from tumor entities other than HNC and limited data from HNC show the potential benefit of anti-MET targeted therapy, especially in combination with other approaches such as IR, cisplatin, and molecular targeted therapy against EGFR. The phenomenon of “oncogene-addiction” described for MET in gastric and lung cancer models has not been reported for any particular oncogene in HNC. Instead, complex signaling networks involving several oncogenes such as MET, EGFR, FGFR and Src, seem to better explain the variable responses to tyrosine kinase inhibitors reported in preclinical HNC models. Unraveling the role of aberrant signaling networks, which could serve as biomarker signatures in given groups of patients, is an imperative step towards the development and implementation of individually-tailored targeted therapies in HNC. The limited translational studies available in HNC potentially indicate that MET may play a more important role in the invasive behavior of these tumors rather than in their initiation and early progression. The gap between the purely preclinical and the more clinically oriented studies is still considerable for HNC, and questions such as the clinicobiological relevance of MET mutations in HNC and the effects of MET signaling on the DNA damage response secondary to IR or cytotoxic drugs, or in hypoxia, still remain largely unanswered. As for the therapeutic relevance of MET in HNC, further characterization of the potential of MET inhibition in combination with other treatment modalities (e.g., IR, cytotoxic drugs, anti-EGFR drugs) remains to be characterized in more relevant preclinical models and in specifically designed clinical trials.

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disease control, showing a potential benefit of cetuximab in combination with radiotherapy only in a certain subsets of patients (Reeves, Hill, Armeson, & Gillespie, 2011). Concerns on increased toxicity when combining cetuximab and radiotherapy have been raised on the basis of several retrospective studies (Pryor et al., 2009; Walsh et al., 2011). Ongoing clinical trials are comparing the use of cetuximab, cisplatin, and radiotherapy in terms of oncological efficiency and toxicity profiles in patients with HNC (trial ID: NCT01216020). The moderate benefit observed with anti-EGFR targeted therapies in HNC in particular, but also in other cancer types, is thought to be largely due to the interplay and crosstalk between RTKs signaling pathways. More particularly, MET and EGFR share multiple downstream targets, primarily related to the PI3K, MAPK and STAT pathways, resulting in a high degree of cooperative and redundant signaling (Guo et al., 2008). When EGFR is inhibited, MET may maintain an intact downstream signaling in most cases, a phenomenon commonly referred to as oncogene bypass (Glickman & Sawyers, 2012). As a consequence, dual inhibition of MET and EGFR results in a more efficient abrogation of downstream signaling than single inhibition of either receptor in HNC cell lines and their derived in vivo xenografts (H. Xu et al., 2011). Concerning biological readouts in these preclinical models, different cell lines show differential responses in regard to cell viability/apoptosis, proliferation, and migration following dual MET and EGFR targeting (H. Xu et al., 2011). Indeed, inclusion of more than one TKI results in very different effects from one cell line to another. For instance, Singleton et al. (2013) showed that three HNC cell lines, UM-SCC-1, UM-SCC-8, and UM-SCC25, strongly rely on EGFR, FGFR, and MET for maximal growth. Consequently, effective growth inhibition was achieved using TKIs against these three receptors, and triple inhibition was significantly more effective on cell growth than combinations that included only two TKIs (Singleton et al., 2013). Conversely, single treatment with an EGFR inhibitor in the EGFR-dependent MSK-921 HNC cell line reached maximal growth inhibition, without any additive effect when using MET and/or FGFR inhibitors (Singleton et al., 2013). It seems plausible to speculate that the translational lecture of these preclinical findings is that only selected patients will benefit from “multitargeted therapy”, while in others the use of several TKIs may merely result in increased toxicity. The crosstalk between EGFR and MET is not restricted to their common downstream targets, since EGFR can equally phosphorylate MET in a SF/HGF-independent manner, for instance through the activation of the non-receptor tyrosine kinase Src (Stabile et al., 2013). The signaling network EGFR-MET-Src seems to be particularly relevant in HNC, as it has been shown that MET is a major mediator of resistance to Src and EGFR inhibitors in those tumors (Sen et al., 2011; Stabile et al., 2013). Interestingly, the potential interplay between MET and EGFR has been suggested also on the genomic level, as MET and EGFR can regulate their mutual transcriptional levels (Reznik et al., 2008; H. Xu et al., 2011). Furthermore, Ach et al. (2013) reported that in salivary gland carcinomas MET gene copy number is significantly correlated with EGFR copy number as well as with the loss of PTEN, providing two mechanisms for sustained activation of the PI3K-AKT pathway in these cancers. The ensemble of these observations is illustrative in light of the fact that oncogene networks play an essential role not only in oncogenesis, but also in responses to treatment. It is commonly accepted that an accurate interpretation of tumor dependence on given networks could help guiding the best design for molecular targeted therapies, allowing the most effective oncological control with minimal side effects. In regard to personalized therapy development in HNC, further understanding of these oncogene networks in translationally-relevant models could be a pivotal step (Gerlach et al., 2013).

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