GPCRs: Emerging anti-cancer drug targets

Accepted Manuscript GPCRs: Emerging anti-cancer drug targets

Ainhoa Nieto Gutierrez, Patricia H. McDonald PII: DOI: Reference:

S0898-6568(17)30239-5 doi: 10.1016/j.cellsig.2017.09.005 CLS 8988

To appear in:

Cellular Signalling

Received date: Revised date: Accepted date:

8 September 2017 ###REVISEDDATE### 11 September 2017

Please cite this article as: Ainhoa Nieto Gutierrez, Patricia H. McDonald , GPCRs: Emerging anti-cancer drug targets, Cellular Signalling (2017), doi: 10.1016/ j.cellsig.2017.09.005

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ACCEPTED MANUSCRIPT GPCRs: Emerging Anti-Cancer Drug Targets

Ainhoa Nietoa and Patricia H. McDonalda* The Scripps Research Institute, Department of Molecular Medicine, Jupiter, Florida, USA

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Correspondence to: Patricia H. McDonald.

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*

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Corresponding authors

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Affiliations

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Ainhoa Nieto Gutierrez, PhD The Scripps Research Institute

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Department of Molecular Medicine

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130 Scripps Way Jupiter, FL 33458

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[email protected]

Patricia H. McDonald, PhD

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The Scripps Research Institute

Department of Molecular Medicine 130 Scripps Way

Jupiter, FL 33458 [email protected]

ACCEPTED MANUSCRIPT Abstract G protein-coupled receptors (GPCRs) constitute the largest and most diverse protein family in the human genome with over 800 members identified to date. They play critical roles in numerous cellular and physiological processes, including cell proliferation, differentiation, neurotransmission,

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development and apoptosis. Consequently, aberrant receptor activity has been demonstrated in

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numerous disorders/diseases, and as a result GPCRs have become the most successful drug target class

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in pharmaceuticals treating a wide variety of indications such as pain, inflammation, neurobiological and metabolic disorders. Many independent studies have also demonstrated a key role for GPCRs in

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tumourigenesis, establishing their involvement in cancer initiation, progression, and metastasis. Given

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the growing appreciation of the role(s) that GPCRs play in cancer pathogenesis, it is surprising to note that very few GPCRs have been effectively exploited in pursuit of anti-cancer therapies. The present

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review provides a broad overview of the roles that various GPCRs play in cancer growth and

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development, highlighting the potential of pharmacologically modulating these receptors for the

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development of novel anti-cancer therapeutics.

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Keywords

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GPCR, Signalling, Cancer, Drug Targets, Drug Discovery

ACCEPTED MANUSCRIPT 1. Introduction G protein-coupled receptors (GPCRs), also known as seven transmembrane spanning receptors (7TMRs) constitute the largest family of cell surface proteins with over 800 encoded in the human genome. The primary function of GPCRs is to transduce a wide and diverse array of extracellular

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stimuli such as biogenic amines, peptides, hormones, neurotransmitters, ions, odorants, and photons

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into intracellular signals that regulate a myriad of physiological processes including cell metabolism, cell

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differentiation, growth, neurotransmission, and sensory perception [1].

All GPCRs are characterized by the presence of seven transmembrane spanning α-helices linked

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by three intracellular and three extracellular loop regions, an extracellular amino-terminal domain, and

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an intracellular carboxyl tail. Upon activation by ligand binding to extracellular domains the receptor undergoes ligand-specific conformational changes allowing it to bind to its cognate G protein

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(heterotrimeric ‘αβγ’ guanine nucleotide binding protein) at the plasma membrane which promotes the

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release of guanosine diphosphate (GDP) from the G protein α-subunit in exchange for guanosine triphosphate (GTP), and also dissociation of the GTP-bound α-subunit from the βγ-dimer [2, 3]. The Gα-

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subunit family consists of four sub-families based on sequence similarity; Gαs, Gαi, Gαq/11 and Gα12/13.

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Both Gα subunits and Gβγ-dimers of heterotrimeric G proteins can couple to downstream effector molecules such as activation (Gαs) or inhibition (Gαi) of adenylyl cyclase, or activation of phospholipase

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C (Gαq or Gα11) to regulate distinct cellular signalling cascades that involve second messengers such as cyclic adenosine monophosphate (cAMP) (Gαs or Gαi) and Ca2+ (Gαq or Gα11) leading to a wide variety of cellular and ultimately physiological responses [4, 5]. Following receptor activation most GPCRs typically undergo ligand/agonist-induced desensitization and internalization; events that are mediated by phosphorylation of the agonistoccupied receptor by G protein-coupled receptor kinases (GRKs). Phosphorylation by GRKs facilitates the recruitment of β-arrestin from the cytosol to the receptor at the plasma membrane, where β-arrestin

ACCEPTED MANUSCRIPT sterically interdicts the receptor:G protein interaction and thereby terminates G protein-mediated signalling. β-arrestin then targets the receptor to clathrin-coated vesicle-mediated endocytosis via its direct interaction with clathrin and the adapter protein AP-2 [6, 7]. Historically, all ‘GPCR’ signalling was believed to be mediated exclusively by G proteins and terminated by GRK phosphorylation and β-

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arrestin binding. However, it is now well recognized that many GPCRs can also signal via other

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transduction mechanisms or even have ligand-independent functions, i.e., constitutive activity and/or

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the ability to modulate the function of other proteins through physical association. Whereas β-arrestins were once believed to play an exclusive role in receptor desensitization, it is now appreciated that β-

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arrestins are signalling molecules in their own right and can serve as scaffolds for various signalling

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modules [8-10]. Moreover, as many GPCRs exhibit pleiotropic signalling, once activated they have the capacity to initiate the full range of signalling pathways or, ligand-specific conformational changes in the

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GPCR can selectively promote the activation of a subset of signalling pathways to the exclusion of

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others, (i.e., G protein activation to the exclusion of β-arrestin signalling or vice versa) a phenomenon known as ‘functional selectivity’ or ‘ligand bias’ that leads to unique cellular responses [11-13].

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In addition to normal physiological processes such as those noted above, aberrant

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expression of GPCRs and their ligands are associated with various pathophysiological processes and disease states. For example, GPCRs regulate a broad range of signal transduction pathways and cellular

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processes that are critical for tumour initiation and progression including cell proliferation, apoptosis, stress signalling, immune evasion, invasion, angiogenesis and metastasis [14-16], (Figure 1). The numerous physiological and pathophysiological responses that GPCRs regulate as well as their relative success as tractable drug targets have made GPCRs the most successful pharmaceutical target class. While it is estimated that 30-40% of currently marketed drugs target GPCRs, they target only ~10% of the superfamily that are considered ‘druggable’ (pharmacologically tractable) [17], and only a handful of

ACCEPTED MANUSCRIPT these are oncology drug targets. Thus, the therapeutic potential of GPCRs in general, and notably for cancer is far from exhausted. Table 1 lists currently FDA-approved anti-cancer drugs.

2. The Link between GPCRs and Cancer

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2.1 Aberrant expression and activity of GPCRs

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One of the earliest studies linking a GPCR to tumorigenic activity was reported by Young et al in 1986. Young et al identified the Mas proto-oncogene by its ability to render NIH 3T3 cells tumorigenic in

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nude mice, and furthermore, using computational methods based on hydrophobicity profiles also predicted the Mas oncogene to encode an integral membrane protein containing seven transmembrane

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domains. Mas encodes a typical GPCR and in contrast to most oncogenes, does not harbour activating

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oncogenic mutations, rather the tumorigenic capacity of Mas is due to its overexpression and the excess of circulating or locally produced ligand(s) [18]. There is now compelling evidence that several wild-type

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GPCRs can induce oncogenic transformation that is dependent on an excess of circulating agonists, or

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agonists generated in the tumour microenvironment, which drive tumour progression. Accumulating evidence supports the autocrine and paracrine involvement of specific neuropeptides, mainly

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neurotransmitters and gut hormones, in different cancers. These neuropeptides, including gastrin-

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releasing peptide, endothelin, bradykinin, neuromedin B, neurotensin, gastrin, cholecystokinin, arginine-vasopressin and angiotensin II bind their cognate GPCR triggering a sustained activation that stimulates cell proliferation in various cell types, and have a crucial role in many aggressive human cancers, including small-cell lung cancer (SCLC), pancreatic cancer, head and neck squamous cell carcinoma (HNSCC) and prostate cancer [19]. Shortly after the Mas proto-oncogene was identified, other wildtype GPCRs were identified as having oncogenic potential including the -1B adrenergic receptor. Similar to Mas, the -1B adrenergic

ACCEPTED MANUSCRIPT receptor when overexpressed in RAT-1 or NIH 3T3 fibroblasts induced foci-formation in an agonist dependent manner and these cells were also tumorigenic when injected into nude mice. Moreover, the oncogenic potential of the -1B adrenergic receptor is enhanced when a mutation is introduced that renders the receptor constitutively active (active in the absence of ligand) [20]. Parma et al., later

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provided a direct link between GPCRs harbouring naturally occurring mutations and human cancer with

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the identification of constitutively activating thyroid stimulating hormone receptor (TSHR) mutations in

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~30% of thyroid adenomas [21]. TSHR is also mutated in large intestine, lung and ovarian cancers. More recently, a surprising discovery from cancer genome deep sequencing analyses such as

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that pursued by The Cancer Genome Atlas (TCGA) project (https://cancergenome.nih.gov) revealed that

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mutations in GPCRs and G proteins are a widespread, frequent event in multiple tumour types. It has been found that approximately 20% of all cancers harbour mutated GPCRs, and specific mutations in Gαs

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as well as Gαq and Gα11 where GTPase activity is diminished, leads to constitutive and persistent

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signalling that may drive tumour progression. Gα12/13 has been shown to possess oncogenic activity, however, overexpression alone is sufficient to promote NIH 3T3 cell transformation [22]. Furthermore,

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recent studies suggest that defects in GPCR trafficking, and trafficking machinery can contribute to

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receptor overexpression and aberrant signalling, and thereby contribute to tumour progression [23]. Numerous GPCR studies have since shown that members of this receptor family can regulate

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major signalling pathways that are critical to the growth and survival of cancer cells, as well as for tumour initiation and progression, cellular proliferation, apoptosis, stress signalling, immune evasion, invasion, angiogenesis and metastasis, [14-16, 20, 24-27]. Despite the prevalence of GPCR drug targets in many different therapeutic areas, such as hypertension and cardiovascular disease (angiotensin, and -adrenergic receptor blockers), allergy (histamine receptor blockers), metabolism (glucagon-like peptide 1 receptor agonists, and serotonin 2C receptor agonists) and CNS disorders (dopamine and serotonin receptor modulators), and the fact that their oncogenic potential has been known for > 30

ACCEPTED MANUSCRIPT years, GPCRs have not typically been a major focus for oncology drug discovery. However, recently several GPCR subfamilies have emerged as novel, attractive, therapeutic strategies for the treatment of various malignancies, examples of which are highlighted below.

2.2 Chemokine receptors

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Chemokines constitute a large family of low molecular weight cytokines that were initially

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described based on their ability to induce the directed migration of leukocytes to sites of inflammation or injury. They are also important for the trafficking of haematopoietic stem cells, lymphocytes and

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dendritic cells. In humans, there are approximately 50 chemokine subtypes that are catergorised based on the number and spacing of conserved cysteine residues in their N-termini (i.e. C, CC, CXC, CX3C), and

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likewise, 19 chemokine receptors have been classified according to which chemokine subtype they bind.

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A single receptor can bind multiple chemokines, and conversely, a single chemokine can bind multiple receptors, whereas some chemokine/receptor interactions are highly specific [28].

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Attention has been focused on the chemokine receptors expressed on cancer cells because

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cancer cell migration and metastasis show similarities to leukocyte trafficking. In addition to mediating cellular migration, there is now an extensive body of evidence demonstrating a strong correlation of

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chemokine receptor expression with various cancers and a key role of chemokine receptors in cancer

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metastasis. A report by Muller et al., in 2001 was first to establish a role for chemokine receptors in cancer metastasis [29]. Using quantitative reverse transcription polymerase chain reaction (qRT-PCR) Muller et al found that CXCR4 and CXCR7 were the most commonly upregulated chemokine receptors in breast cancer cells versus normal breast epithelial cells. They also reported that breast cancer cells migrated in vitro in response to CXCR4 and CCR7 ligands (CXCL12 and CCL21 respectively). Furthermore, a CXCR4 blocking antibody inhibited metastasis in a mouse xenograft model using MDA-MB-231 human breast cancer cells [29].

ACCEPTED MANUSCRIPT CXCR4 represents one of the best established chemokine receptors driving cancer metastasis and as mentioned, tumour cells frequently express high levels of CXCR4, while its ligand, CXCL12 (stromal derived factor 1/SDF-1), is expressed in the most frequent sites of metastasis, including the lungs, bone marrow, lymph nodes, and liver [24]. These studies and many more since support the initial

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hypothesis that malignant cells use chemokine receptors to migrate to distant sites of ligand expression

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and that expression of certain receptors is associated with a poor prognosis [30]. Chemokine receptors

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CCR7 and CCR10, have also been shown to participate in metastatic homing of cancer cells [31], and cancer cell survival and growth [32]. Other chemokine receptors, including CXCR3, are implicated in

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several malignancies as biomarkers of tumour behaviour as well as potential therapeutic targets [33].

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Other chemokines, including CCL2, CCL5, and CXCL8/IL-8, through their respective GPCRs, recruit leukocytes and macrophages to the tumour site, which in turn can release vascular endothelial growth

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factor (VEGF) and other angiogenic factors that contribute to the growth of new blood vessels and

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tumour progression [15, 34].

To address these issues, considerable effort has been focused on discovery and development of

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small-molecule chemokine receptor antagonists. The first in class CXCR4 competitive antagonist,

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AMD3100 (plerixafor, MozobilTM), more accurately described as a CXCR4 partial agonist [35], was approved by the FDA in 2008 for the mobilization of hematopoietic stem cells in patients with multiple

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myeloma and non-Hodgkin lymphoma. More recently, monoclonal antibodies (mAbs) targeting chemokines and their receptors have been pursued for therapeutic purposes. Ulocuplumab (BMS936564 / MDX1338), a fully human anti-CXCR4 antibody, induces cell death in chronic lymphocytic leukemia [36]. Monoclonal antibodies directed at other chemokine receptors have also shown effectiveness in different xenograft models of cancer [37-42].

ACCEPTED MANUSCRIPT 2.3 Protease-activated receptors (PARs) Protease-activated receptors (PARs) are a subfamily of GPCRs that are activated by a unique proteolytic cleavage mechanism. Serine proteases irreversibly cleave the receptors at a specific site within their extracellular N-terminus to expose a new, non-diffusible, N-terminal tethered ligand domain

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that binds and activates the cleaved receptor. Four types of PAR receptors (PAR1-4) have been cloned,

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and classified according to the serine proteases that activate them, i.e., thrombin acts on PAR1, 3 and 4

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whereas trypsin, and other proteases with trypsin-like specificity such as tryptase, and tissue factor (TF) act on PAR2 [43]. Proteolytic cleavage typically leads to autoactivation of the receptor, however

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different receptor crosstalk mechanisms such as transactivation contribute to the high diversity of PAR

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signalling and physiological effects [44].

PARs together with their protease activators play important roles in vascular physiology, neural

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tube closure, inflammation, hemostasis (bleeding stoppage) and cancer progression. Coagulant factors

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and proteases such as TF and thrombin respectively present in the tumour microenvironment have been shown to play a pivotal role in tumour invasion, and metastatic efficiency [45]. Thrombin effects on

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tumour cells appear to be mostly PAR-mediated. PAR1 is aberrantly expressed in a variety of tumour

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types including breast, lung, ovarian, and prostate, and its overexpression correlates directly with greater invasiveness and the development of metastases [45-47]. Moreover, in patients with liver [48],

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gastric [49], or breast cancer [50], PAR-1 expression was an unfavourable prognostic factor correlating with poor survival outcome. However, pepducin-mediated blockade of PAR1 in preclinical breast cancer animal models inhibited tumour growth and metastases to the lung [51]. Furthermore, siRNA knockdown of PAR1 also resulted in decreased tumour growth and metastases to the lung in a melanoma animal model [52]. PAR1 and PAR2 are present in multiple cancer cell types, and several lines of evidence also highlight an active role for PAR2 in tumor progression development. For instance, PAR2 knock-out mice

ACCEPTED MANUSCRIPT displayed delayed breast tumor development that resulted in decreased metastases [53], and in agreement with these observations, blocking antibodies targeting PAR2 attenuated tumour growth and metastasis in breast xenograft models [54]. Moreover, shRNA-mediated silencing of PAR2 in breast cancer cells prevented PAR2-dependent malignant cell phenotype [55].

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Hence, both PAR1, and PAR2 antagonism have potential as therapeutic strategies to treat

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various cancers. However, owing to the distinct activation mechanism of the individual receptors, and

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the complex relationship between these PARs i.e., PAR1 transactivation of PAR2, pharmacological intervention has proven extremely challenging. Thus, the only clinical agent that has emerged after

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decades of pursuing pharmacological inhibition of PARs is the small molecule PAR1 competitive

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thrombotic cardiovascular related events [56].

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antagonist, SCH530348 (vorapaxar, ZontivityTM) that gained FDA approval in 2014 for the prevention of

2.4 Lysophospholipid Receptors

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Lysophopholipids (LPs), are a family of endogenous lipid-signalling molecules and second

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messengers that include lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P), and regulate a myriad of cellular events such as cell survival, motility, chemotaxis, apoptosis, proliferation,

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differentiation and malignant transformation. LPs exert their biological activities mostly through ~40

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GPCRs, including six LPA receptors (LPA1-LPA6), five S1P receptors (S1P1-SIP5) as well as newly identified receptors for lysophosphatidyl inositol (LPI1) and lysophosphatidyl serine (LYPS1-LYPS3) [57]. LPAs possess mitogenic, motogenic, and anti-apoptotic properties that collectively, enhance cell survival. Given these properties and the numerous cellular processes that LPA/LPARs regulate, it’s not surprising that aberrant LPA/LPAR signalling occurs in various cancers including ovarian [58], breast [59], colon [60], and pancreatic tumours [61, 62]. However, the role of LPA receptor subtypes differs between cancer cell types. For example, LPA1 has widespread expression and plays a role in driving cell motility

ACCEPTED MANUSCRIPT and metastasis in cancer pathogenesis [63]. Inhibition of LPA1 using a small-molecule LPA1/LPA3 antagonist (Ki16425) was shown to inhibit tumour growth, and attenuate invasion and metastasis of pancreatic cancer to the liver, lung, and brain in pancreatic cancer cell-inoculated nude mice [64]. LPA2 has more restricted expression and is barely detectable in normal epithelial cells but is highly

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upregulated in various malignancies including ovarian and colon cancers, and furthermore, its

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expression correlates with invasiveness [65, 66].

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Like LPA1, LPA4 is widely distributed with high expression levels in brain, platelets, adipose tissue, ovary, uterus and placenta [67]; in contrast to LPA1, LPA4 is a negative regulator of cell motility.

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When co-expressed in endogenous LPA receptor-deficient B103 neuroblastoma cells, activation of LPA4

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opposed migration and invasion promoted by LPA1 revealing functional antagonism between the two receptors [68]. Hence, LPA1 and LPA2 antagonism may have utility in preventing metastases and tumour

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progression respectively, whereas selective LPA4 agonism would be required to provide similar benefit.

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Bioactive lipids such as S1P and its cognate receptors (S1P1-S1P5) are involved in multiple cellular processes such as cell proliferation, differentiation, trafficking, and cell survival, and play

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significant roles in vascular development, angiogenesis, immunity, and chemotaxis. SIPRs vary in their

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tissue distribution where S1PR1-3 receptors are expressed throughout the immune, central nervous, and cardiovascular systems; S1PR4 is primarily expressed in lymphoid tissue; and S1PR5 is a

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predominant receptor in the brain, and spleen [69]. S1PRs also play a significant role in the progression of various cancers, regulating processes such as, inflammation, which can drive tumourigenesis, and neovascularization of the tumour micro-environment that provides nutrients and oxygen facilitating tumour growth and survival [70]. However, much like the LPA/LPARs described above, the role of S1P and S1P receptor subtypes varies between different cancers [71]. For instance, migration of fibrosarcoma cells is mediated by S1P-activated S1P1R [72], whereas, migration of gastric cancer cells is mediated by S1P3R [73]. In contrast, activation of S1P2R mediates inhibition of cell motility of

ACCEPTED MANUSCRIPT glioblastoma cells [74]. Moreover, S1P receptor expression in tumours has been correlated with the development of chemotherapeutic resistance and patient survival (reviewed in [75]). In this regard, high expression of S1P1R and S1P3R in tumours from estrogen receptor positive (ER+) breast cancer patients is associated with increased resistance to chemotherapeutic agents and shorter disease-specific survival

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[76].

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Efforts to develop highly specific and efficacious S1PR targeted drugs has resulted in the recent

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success of the first-in-class S1P1 receptor modulating drug, FTY720 (Fingolimod, Gilenya ®) FYT720 is a small molecule, functional antagonist of S1P1R that blocks immune cell trafficking and was approved in

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2010 for the treatment of multiple sclerosis. FTY720 has also demonstrated efficacy in numerous in vitro

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and in vivo cancer models, and shown to have chemo-sensitizing properties suggesting therapeutic potential in cancer patients (reviewed in [77]), however, its strong immunosuppressive effects currently

2.5 E Prostanoid (EP) Receptors

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limit its clinical utility.

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Prostaglandins (PGs) and thromboxane A2 (TXA2) are bioactive lipids generated by the action of cyclooxygenases (COX-1 and COX-2) on arachidonic acid [78]. PGs are produced in response to various

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physiological and pathological stimuli and play essential roles in maintaining body homeostasis.

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Prostaglandin E2 (PGE2) is the most widely produced prostanoid in the human body and plays a major role in various processes such as, bone healing, regulation of gastrointestinal mucosa, embryo implantation, vasodilatation, pain, and inflammation - a basic innate immune response to perturbed tissue homeostasis. Hence COX inhibitors such as the non-steroidal anti-inflammatory drugs (NSAIDs), like acetylsalicyclic acid (Aspirin™), or the more recent COX-2 selective inhibitors (coxibs), such as meloxicam (Mobic™), are used for symptomatic treatment of inflammatory diseases together with pain relief.

ACCEPTED MANUSCRIPT An association between inflammation and the development of cancer is well-established. Importantly, expression of the inducible COX isoform, COX-2, has been found to correlate with cancer progression in experimental models and in many types of cancers, and pharmacological inhibition or genetic ablation of COX-2 reduces tumour cell proliferation and metastasis [79]. Moreover, long-term

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administration of anti-inflammatory agents (NSAIDs or coxibs) can exert significant chemoprevention

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against certain cancers [80]. Hence, in addition to the anti-inflammatory and analgesic properties, COX-

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2 inhibition has emerged as a potential therapeutic approach in certain cancers. However, FDAapproved COX-2 inhibitors have either been removed from the market (in the case of rofecoxib; Vioxx™)

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or have black box warnings (celecoxib; Celebrex™) due to risk of cardiovascular side effects [81], fuelling

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the search for alternative approaches to block COX-2/PGE2–associated effects. PGs exert their biological activity mainly through four E prostanoid receptors (EP1-EP4), which

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exhibit differential patterns of tissue distribution. EP1 is ubiquitously expressed, while EP3 receptor

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expression is high in adipose tissues, pancreas, kidney and vena cava. EP4 is mainly expressed in the gastrointestinal tract, uterus, hematopoietic tissues and skin, whereas EP2 receptor is the least

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abundant EP receptor. PGE2 binding to these receptors can promote different biological effects

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depending on which EP receptor subtype is activated and the cell-type in which it’s expressed [82, 83]. Many biological effects of PGE2 are mediated by EP4. This receptor is the most widely expressed

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in the body and is implicated in inflammation, modulation of tissue development and regeneration, and regulation of vascular tone and haemostasis, among others [84]. The involvement of EP4 receptors in tumorigenesis of multiple malignancies is well established [85-87]. For example, In breast cancer patients, EP4 expression correlated with enhanced lymphatic invasion [88], whereas EP4 antagonists attenuated lung metastasis of these breast tumour cells in mice [89, 90]. Furthermore, colon carcinogenesis was inhibited in mice lacking EP4, and by the EP4 antagonist ONO AE2-227 [91]. Although EP4 is the most widely studied prostanoid receptor in cancer, other EP receptors have also been shown

ACCEPTED MANUSCRIPT to play a role in cancer pathogenesis. Early studies with EP1 knockout mice suggested an important role for this receptor in colon cancer, obtaining similar results in wild type mice given an EP1 antagonist [92]. The EP2 receptor is involved in angiogenesis by promoting the expression of VEGF [93, 94]. The EP3 receptor, although least commonly linked to cancer, may play an indirect role regulating pathways that

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contribute to angiogenesis [95-97].

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Hence, the potential for exploiting the EP receptors as therapeutic targets for the treatment of

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cancer and metastatic disease is clear [98] and some drug candidates have already progressed to clinical trials, such as AAT-007 (RQ-00000007), an EP4 receptor antagonist that entered Phase II in January 2017

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for advanced solid tumours in prostate, breast and non-small cell lung cancer (NCT02538432).

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2.6 Smoothened (SMO) Receptor

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In vertebrates, the Hedgehog (HH) gene family encodes three glycoproteins; Sonic (SHH), Indian (IHH), and Desert (DHH) that are expressed in different tissues and at different stages of embryogenesis

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and early development. SHH is the most potent of these ligands, and following secretion binds to and

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inactivates the twelve transmembrane spanning Patched receptor (PTCH) which in turn relieves PTCHmediated repression of the Smoothened receptor (SMO), a GPCR and key mediator of the SHH signalling

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pathway [99, 100]. Activation of SMO via inhibition of PTCH leads to activation of the glioma-associated

[101-103].

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oncogene (Gli) family of zinc finger transcription factors that induce transcription of HH target genes

In adults, HH signalling contributes to stem cell proliferation, and tissue repair and organ regeneration, whereas dysregulation of the HH signalling pathway (achieved by inactivating mutations of PTCH, constitutive activation of SMO, or gene amplification of Gli), plays a critical role in the initiation and progression of a variety of human malignancies including, basal cell carcinoma (BCC), malignant gliomas, medulloblastoma, leukemias, and cancers of the breast, lung, pancreas, and prostate [104,

ACCEPTED MANUSCRIPT 105]. In addition to tumorigenesis, and tumour progression, emergent resistance to targeted therapeutics has also been shown to be influenced by the SHH signalling pathway [106]. Hence, key regulators of HH signalling are regarded as important targets for cancer therapeutics, however, owing to its ‘druggable’ nature, most efforts have been devoted towards pharmacologically targeting SMO, and

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to date, two SMO inhibitors, vismodegib (Erivedge®) and sonidegib (Odomzo®), have received FDA

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approval (2012, and 2015 respectively), for the treatment of locally advanced, and metastatic BCC [107-

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111]. SMO inhibitors are currently being evaluated as targeted therapies in a variety of other cancers.

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2.7 Frizzled (FZD) Receptors

The Wnt family of secreted glycoproteins of which there are 19 members mediate their

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signalling through a class of GPCRs known as Frizzled receptors (Fzd 1-10). The Wnt/Fzd interaction is

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highly promiscuous; a single Wnt ligand can bind multiple Fzd receptors rendering Wnt/Fzd signalling intriguingly complex. The Wnt signalling pathway is highly conserved across species and regulates critical

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aspects of cell proliferation, stem cell differentiation, polarity, cell fate determination and development.

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In humans, dysregulation of the pathway is related to developmental alterations, as well as numerous diseases, among which are various types of cancers (for review [112, 113]). The canonical Wnt signalling

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pathway involves the intermediate signalling molecule β-catenin, and this pathway has long been

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implicated in cancer. Non-canonical Wnt signalling includes both the Ca2+/PKC pathway, and the planar cell polarity pathway (PCP) pathway mediated via JNK signalling [114, 115]. Wnt signalling plays a critical role in the development and maintenance of cancer stem cells (CSCs), a population of cells that maintain a tumour via the stem cell process of self-renewal [116]. While it is apparent that dysregulation of Wnt signalling is a driver in many human cancers, finding a vulnerable point of therapeutic intervention has been challenging. As such, development of cancer therapies that specifically or indirectly target CSCs may decrease the risk of drug resistance, metastases,

ACCEPTED MANUSCRIPT and disease relapse. Fzd7 is the most commonly upregulated Wnt receptor in a variety of cancers and thus is an attractive target for anti-cancer therapy. The mAb Vantictumab (OMP-18R5), initially identified by binding to and blocking Fzd7, and found to interact with five other Fzd receptors [117], has been demonstrated to block the canonical Wnt pathway and consequently inhibit tumour growth and

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tumour initiation. Thus, targeting the Wnt pathway by inhibiting multiple members of the Fzd receptor

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family is a promising anti-cancer strategy and Vantictumab has already reach Phase 1b clinical trials for

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pancreatic, non-small cell lung cancer (NSCLC), and breast cancer (NCT01345201, NCT02005315,

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NCT01973309, NCT01957007) [118].

2.8 Multiple GPCRs regulate Hippo Signalling

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The Hippo signalling pathway plays an essential role in orchestrating cell proliferation, growth,

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apoptosis and autophagy to establish and maintain exquisite control of organ size. The core of the mammalian Hippo signalling pathway is comprised of the serine/threonine kinases MST1 and 2

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(mammalian Ste2-like kinases) which activate kinases LATS1 and 2 (large tumour suppressor kinase 1/2)

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that then phosphorylate the transcriptional coactivators YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif). Phosphorylated YAP and TAZ are retained in the

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cytosol thereby inhibiting their transcriptional activity. Upon dephosphorylation, YAP and TAZ

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translocate to the nucleus to induce expression of growth-promoting genes [119, 120]. As the Hippo pathway regulates YAP and TAZ activity generally by preventing their access to the nucleus, inappropriate inhibition or loss of Hippo signalling induces both tissue and organ overgrowth, furthermore dysregulation of this pathway is strongly associated with a broad spectrum of cancers including colorectal, liver, lung, and ovarian cancer, melanoma, and leukaemia [121-123]. Multiple upstream modulators of the Hippo pathway have been identified including a number of different GPCRs, and depending on the G protein that the receptor couples to, YAP and TAZ activity can

ACCEPTED MANUSCRIPT either be induced or blocked (for review [124, 125]). For example, LPA stimulates GPCRs that couple to Gα12 and Gα13, and, even though it was found to have no effect on MST1/2 activity, it inhibits activation of LATS1/2 promoting YAP nuclear accumulation and YAP-mediated transcriptional activity [125]. Conversely, inhibition of the LPA receptor blocked LPA-induced activation of YAP. Assessment of various

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GPCRs showed that activation of those that couple to Gα12/13, Gαq/11, or Gαi/o led to YAP

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dephosphorylation, whereas those that couple to Gαs, including the 1 adrenergic receptor, induced

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YAP phosphorylation preventing YAP nuclear accumulation and YAP-mediated transcriptional activation [126].

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In addition to the GPCRs mentioned above, Wnt and HH signalling pathways have also been

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shown to engage in crosstalk with the Hippo signalling pathway, implicating GPCRs such as Fzd and SMO in modulating Hippo signalling [127, 128]. Together, these observations demonstrate that GPCRs are

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important regulators of Hippo-YAP signalling and suggest that modulation of the Hippo signalling

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pathway via GPCRs may be a useful therapeutic strategy in certain cancers.

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2.9 Orphan GPCRs as oncology drug target

Although GPCRs represent the most predominant therapeutic targets, the fundamental biology

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and drug discovery potential of a large portion of these receptors remains to be explored [128]. Of the

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~360 GPCRs that are considered ‘druggable’, ~240 are classified as known receptors and are activated by ~70 known ligands, while ~120 are described as ‘orphan’ receptors (oGPCRs) whose endogenous ligand(s) remain to be identified [129]. Studies examining oGPCR distribution and localization, as well as studies probing the behavioural phenotype of animals lacking specific oGPCRs, have been central to establishing their therapeutic potential. Consequently numerous oGPCRs have been linked to cancer development and progression on the basis of their overexpression and/or up-regulation [130, 131] and

ACCEPTED MANUSCRIPT hence have emerged as promising candidates for the development of novel anticancer therapeutic strategies. Utilizing genomic information derived from breast cancer patients Feigin et al [132] discovered that the oGPCR, GPR161, is overexpressed specifically in triple negative breast cancer (TNBC); a subset

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of breast cancer with poor prognosis owing to the lack of effective targeted therapies. Patients

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expressing higher levels of GPR161 were found to have an increased probability of disease relapse.

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Furthermore, overexpression of GPR161 in human non-transformed mammary epithelial cells increases cell proliferation and induces cell migration and invasion of cells in 3D culture. These results suggest that

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GPR161, in addition to providing prognostic value may also serve as a potential drug target in TNBC.

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Another oGPCR, found to be up-regulated in human tumours is GPR49 [133]. This oGPCR is overexpressed in both colon and ovarian tumours, and of note, the expression level of GPR49 increased

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in these tumours as the tumours advanced implicating a role for GPR49 in tumour progression. The

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screening of a DNA microarray database of human BCC cases revealed elevated GPR49 mRNA levels in 95% of the cases [134] and overexpression of GPR49 in human keratinocyte HaCaT cells promoted cell

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proliferation. Moreover, transplantation of HaCaT GPR49 expressing HaCaT cells into nude mice induced

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tumour formation.

Melanoma is the most aggressive human skin cancer and GPR18 was found to be one of the

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most abundantly expressed oGPCRs in melanoma metastases and in numerous melanoma cell lines [135]. Subsequent functional experiments in melanoma cells indicated that GPR18 has intrinsic constitutive activity and may play a role in inhibition of apoptosis in melanoma metastases indicating an important role for GPR18 in tumour cell survival. Conversely, GPR56 was found to inhibit prostate cancer progression, and suppress tumour growth and metastasis in melanoma xenografts [136]. Moreover, GPR56 inhibited VEGF production from melanoma cells and prevented melanoma angiogenesis and growth [137]. Accordingly, the expression of GPR56 has been found inversely

ACCEPTED MANUSCRIPT correlated with melanoma malignancies, suggesting its potential role in cancer development and metastasis [130, 137]. Collectively, these studies strongly suggest that these oGPCRs (and others) may serve as suitable targets for anti-cancer treatment of various cancers and further studies to identify their

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natural ligands and role(s) in normal and pathological processes is highly warranted.

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3. GPCR Transactivation of RTKs

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In addition to the aforementioned, well-characterized GPCR signalling pathways, it has been known for over two decades that GPCRs can also mediate signal transduction events downstream of

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receptor tyrosine kinases (RTKs) via a process known as ‘transactivation’. RTKs are a family of single

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transmembrane receptors comprised of 58 members that possess intrinsic kinase activity; binding of cognate ligands promotes receptor dimerization and tyrosine autophosphorylation. Like GPCRs, RTKs

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regulate vast signalling networks, and are involved in a wide variety of biological processes such as cell

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division and cell death. In 1996, Ullrich and colleagues discovered that treatment of RAT-1 cells with GPCR agonists, endothelin-1, LPA or thrombin led to the activation and downstream signalling of the

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Epidermal Growth Factor (EGF) Receptor (EGFR) resulting in ERK1/2 (MAPK) phosphorylation; a signalling

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event that is also downstream of direct EGFR activation. This observation suggested that intracellular crosstalk between the RAT-1 endogenous GPCRs and EGFR led to transactivation of EGFR i.e., RTK

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activation in the absence of its cognate ligand [138]. In addition to intracellular crosstalk, multiple mechanisms for the transactivation of EGFR by various GPCRs have been proposed and reviewed extensively elsewhere [139-141]. As mentioned, EGFR controls a wide variety of biological responses such as cell proliferation, differentiation, migration and the modulation of apoptosis [142, 143]. Aberrant EGFR activation due to overexpression, mutation, or autocrine signalling is frequently implicated in hyperproliferative diseases such as cancer. Hence EGFR family members are overexpressed in lung [144], breast [145, 146] and

ACCEPTED MANUSCRIPT prostate [147] cancer, and a mutated EGFR (EGFRvIII) is expressed in 30% of glioblastomas [148, 149]. Such expression is linked to aggressive disease and poor prognosis. These findings together with extensive literature on EGFR and its ligands in tumour cell lines and clinical specimens have made EGFR an important molecular target for drug discovery. In addition to dysregulated EGFR activity, numerous

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reports also support a role for GPCR transactivation of EGFR in various cancers including lung [150],

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breast [151, 152], ovarian [153, 154] and glioblastoma [155].

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Since the original observation by Ullrich and colleagues, there have been numerous reports of GPCRs that can ‘transactivate’ RTKs. Although the EGFR is the most-widely studied in this regard other

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RTK family members such as vascular endothelial growth factor(VEGF) receptor (VEGFR) [156, 157],

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platelet-derived growth factor receptor (PDGFR) [158, 159] and insulin growth factor-1 receptor (IGFR) [160, 161] have all been shown to be ‘transactivated’ by GPCRs, and furthermore have all been strongly

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implicated in the cancer phenotype. Moreover, the concept of transactivation by GPCRs can be

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expanded to include serine/threonine kinase receptors such as the Transforming Growth factor - (TGF) receptor (TR1) [162] which has also been implicated in carcinogenesis [163, 164]. The ability of the

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GPCRs to transactivate protein kinase receptors not only expands the repertoire of signalling

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attributable to GPCRs, but in instances where the protein kinase receptor response is due to GPCR transactivation, suggests that the therapeutic target may well be the upstream GPCR [165]. For example,

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it has been shown that Angiotensin type 1 receptor (AT1R) may couple to malignancy through the transactivation of EGFR [166, 167] and different AT1R antagonists have demonstrated efficacy as antitumorigenic agents indirectly acting on EGFR [168-170]. Collectively, these reports strongly suggest an important and broad role for GPCR-EGFR cross-talk and highlight the importance of multiple signalling networks in the pathophysiology of cancer and the potential of certain GPCRs to provide novel strategies for the treatment of RTK-driven tumours.

ACCEPTED MANUSCRIPT 4. A Plethora of Possibilities

From a drug discovery perspective, the most intuitive approach to offset the pro-malignancy effects of aberrant GPCR signalling is to use drugs with negative efficacy i.e., antagonists that block agonist activity, or inverse agonists for those receptors exhibiting constitutive activity, but as mentioned

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previously GPCR agonists also have their place in cancer therapeutics [68, 136]. Historically, ligands/drugs targeting GPCRs were believed to block (agonists/inverse agonist) or promote (agonists)

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all signalling pathways downstream of a given receptor, however, our understanding of GPCR signaling has

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expanded beyond the simplel paradigm, where the signaling cascade was assumed to be linear, to include G protein independent signaling [171], receptor crosstalk [172], functional selectivity [173], and allosteric

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modulation [174]. Functional selectivity or ‘ligand bias’ refers to the phenomenon whereby, various ligands of the same receptor can stabilize distinct receptor conformations and preferentially activate/modulate a

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subset of signaling pathways to the exclusion of others. Allosteric modulators are ligands that bind to

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sites topographically distinct from the orthosteric site, and with little to no intrinsic activity of their own, induce conformational changes of receptors that can either enhance or attenuate the potency and/or

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efficacy of the endogenous orthosteric ligand. Thus allosteric modulation, and functional selectivity are

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two very exciting areas in GPCR receptor pharmacology that offer novel modes of efficacy that can be used to fine-tune receptor activity and exploited in GPCR-targeted cancer drug discovery and GPCR drug

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discovery in general.

Although currently, the majority of drugs targeting this intriguing receptor family are mainly small molecules, GPCRs can be modulated by a range of exogenous ligands including, peptides (GLP1R peptide modulators representing the largest group of therapeutics targeting GPCRs) [175], and antibodies, with mAbs gaining a lot of traction [176]. For example mogamulizumab (KW-0761; PoteligeoTM) is a mAb targeting the CC chemokine receptor 4 (CCR4) that was recently granted ‘Breakthrough Therapy’ status from the FDA for the treatment of adult T cell leukaemia-lymphoma

ACCEPTED MANUSCRIPT [177]. In contrast to small-molecule drugs, the high selectivity of peptides or proteins to their targets may reduce side effects and toxicity to normal cells [178]. In addition to identifying novel GPCR targets, and/or novel approaches to modulating these receptors for the development of anti-cancer therapeutics, known drugs targeting GPCRs may be

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repurposed for the treatment of cancer. For example, β-blockers that inhibit beta-adrenergic receptor

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activity are a class of commonly prescribed drugs used in the treatment of hypertension, cardiac heart

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failure, and arrhythmias , and recent retrospective and epidemiologic studies strongly support the notion that β-blockers may have beneficial effects on cancer progression, metastasis, and mortality (15–

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24). Indeed, these studies have led to the initiation of clinical phase II studies evaluating the effect of

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administering propranolol to ovarian, cervix, colorectal, and breast cancer patients (ClinicalTrials.gov identifiers: NCT01504126, NCT01308944, NCT01902966, NCT00888797, and NCT01847001). Other

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known GPCR-targeted non-oncology drugs are also currently being evaluated as novel cancer

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therapeutic agents [179]. Lastly, GPCRs exhibiting aberrant expression in various malignancies also present themselves as potential biomarkers providing not only possible drug targets but also diagnostic

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and prognostic value.

5. Conclusion

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The GPCR subfamilies and the roles they play in cancer pathogenesis described above offer only a snapshot of the possibilities for exploiting GPCRs for the treatment and prevention of cancer. However, the current state of the literature and clinical data suggests enormous promise and unprecedented opportunities for the potential of GPCR modulators in cancer therapeutics. Ever since the discovery in 1986 of the transforming activity of the GPCR, Mas, overwhelming evidence has been accumulating demonstrating that GPCRs play critical roles in mediating many aspects of tumourigenesis including cancer initiation and progression. Moreover, recent, genomic analyses have uncovered GPCR

ACCEPTED MANUSCRIPT mutations, copy number alterations, and gene expression changes in a wide variety of cancers. Indeed, pharmacological strategies targeting GPCRs have become increasingly attractive as more data associating GPCRs with various malignancies have emerged. Although more work needs to be done to understand the molecular mechanisms by which GPCRs influence cancer progression and is thus of

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critical importance to their utility as oncology drug targets, our increasing knowledge of the expression

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patterns and functional activity of GPCRs in different types of cancer, along with the well-established

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‘druggability’ of this particular class of cell-surface receptors, place GPCRs front and centre for novel

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oncology drug-development efforts.

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Acknowledgements

We would like to thank Dr. Derek Duckett for helpful discussion and critical reviewing of the

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manuscript, and Ms. Amparo Escolano for her assistance with graphics.

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ACCEPTED MANUSCRIPT Figure 1. Summary of GPCRs and their role(s) in cancer progression; inflammation and immune tolerance, cancer cell proliferation and survival, angiogenesis, migration, invasion and metastasis.

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Table 1. Selected FDA-approved anti-cancer drugs targeting GPCRs.

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Fig. 1

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Type of molecule

Receptor

Cancer

Mogamulizumab

Humanized Monoclonal Antibody

CCR4

· Relapse or refractory ATL · Relapse or refractory CTCL · Peripheral T-cell lymphoma

Plerixafor

Small Molecule

CXCR4

· Stem cell mobilization in nonHodgkin's lymphoma and multiple myeloma

Sonidegib

Small Molecule

SMO

· BCC

Vismodegib

Small Molecule

SMO

· BCC

Cabergoline

Small Molecule

D1R

Lanreotide

Peptide

SSTR

Degarelix

Peptide

GnRH

· Pituitary tumors · Neuroendocrine tumors from the gastrointestinal tract or the pancreas · Prostate cancer

Raloxifene

Small Molecule

ER

Brigatinib

Small Molecule

· ALK · EGFR

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· Reduce the risk of invasive breast cancer · ALK-positive NSCLC

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Ligand

ACCEPTED MANUSCRIPT Highlights

Many independent studies have demonstrated a key role for GPCRs in cancer

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GPCRs are the most successful pharmaceutical target class yet only a handful of these are

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development of novel anti-cancer therapeutics.

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This review highlights the potential of pharmacologically modulating these receptors for the

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oncology drug targets.