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mTOR pathway as a therapeutic target in ovarian cancer
YGYNO-975797; No. of pages: 7; 4C: Gynecologic Oncology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer Seiji Mabuchi ⁎, Hiromasa Kuroda, Ryoko Takahashi, Tomoyuki Sasano Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
H I G H L I G H T S • PI3K/AKT/mTOR pathway is frequently mutated or activated in ovarian cancer. • PI3K/AKT/mTOR pathway plays a crucial role in the progression of ovarian cancer. • P3K/AKTmTOR inhibition might be an effetive treatment for ovarian cancer.
a r t i c l e
i n f o
Article history: Received 17 December 2014 Accepted 2 February 2015 Available online xxxx Keywords: PI3K AKT mTOR mTORC1 mTORC2 Ovarian cancer
a b s t r a c t The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway plays a critical role in the malignant transformation of human tumors and their subsequent growth, proliferation, and metastasis. Preclinical investigations have suggested that the PI3K/AKT/mTOR pathway is frequently activated in ovarian cancer, especially in clear cell carcinoma and endometrioid adenocarcinoma. Thus, this pathway is regarded as an attractive candidate for therapeutic interventions, and inhibitors targeting different components of this pathway are in various stages of clinical development. Here, we highlight the recent progress that has been made in our understanding of the PI3K/AKT/mTOR pathway and discuss the potential of therapeutic agents that target this pathway as treatments for ovarian cancer and the obstacles to their development. © 2015 Elsevier Inc. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . PI3K/AKT/mTOR signaling pathway . . . . . . . . . . . . . . . . Alteration of the PI3K/AKT/mTOR pathway in ovarian cancer . . . . . Inhibitors of the PI3K/AKT/mTOR signaling pathway . . . . . . . . . PI3K inhibitors . . . . . . . . . . . . . . . . . . . . . . . Pan-class I PI3K inhibitors . . . . . . . . . . . . . . . Isoform-selective PI3K inhibitors . . . . . . . . . . . . Dual PI3K/mTOR inhibitors . . . . . . . . . . . . . . AKT inhibitors . . . . . . . . . . . . . . . . . . . . . . . mTOR inhibitors . . . . . . . . . . . . . . . . . . . . . . . Rapamycin and its analogs . . . . . . . . . . . . . . . ATP-competitive inhibitors . . . . . . . . . . . . . . . . . . Metformin . . . . . . . . . . . . . . . . . . . . . . . . . Clinical trials of PI3K/AKT/mTOR inhibitors in ovarian cancer . . . . . Phase I trial of an AKT inhibitor . . . . . . . . . . . . . . . . Phase II trial of an mTORC1 inhibitor . . . . . . . . . . . . . Resistance to PI3K/AKT/mTOR inhibitors . . . . . . . . . . . . . . Future directions . . . . . . . . . . . . . . . . . . . . . . . . . Combining PI3K/AKT/mTOR inhibition with other targeted agents
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Abbreviations: CCC, clear cell carcinoma; SAC, serous adenocarcinoma; mTOR, mammalian target of rapamycin; mTORC, mTOR complex; S6K-1, ribosomal S6 kinase-1; 4E-BP1, elF4E binding protein 1; PI3K, phosphatidylinositol 3-kinase; cisplatin, cis-diaminodichloroplatinum; PTEN, phosphatase and tensin homolog deleted on chromosome 10. ⁎ Corresponding author at: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Fax: +81 6 68 79 3359. E-mail address: [email protected] (S. Mabuchi).
http://dx.doi.org/10.1016/j.ygyno.2015.02.003 0090-8258/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Mabuchi S, et al, The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer, Gynecol Oncol (2015), http:// dx.doi.org/10.1016/j.ygyno.2015.02.003
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S. Mabuchi et al. / Gynecologic Oncology xxx (2015) xxx–xxx
Patient selection . . . . . . . . . Potential as chemopreventive agents Conclusions . . . . . . . . . . . . . Conflicts of interest statement . . . . . References . . . . . . . . . . . . . .
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Introduction It is estimated that more than 225,500 women worldwide are diagnosed with ovarian cancer each year [1]. Ovarian cancer is a heterogeneous disease that can be categorized into various histological subtypes: high-grade serous, low-grade serous, clear cell, endometrioid, and mucinous adenocarcinoma. Each histological subtype is associated with a distinct clinical behavior and molecular pattern, but historically ovarian cancer has been treated with a single entity. The current standard treatment for newly diagnosed ovarian cancer is a combination of cytoreductive surgery and platinum-based combination chemotherapy [2]. Despite recent advances, as more than two-thirds of ovarian cancer cases are diagnosed at an advanced stage ovarian cancer patients are still at significant risk of recurrence, which cure is generally difficult with current standard treatments [2]. As a result, ovarian cancer remains a leading cause of gynecological cancer mortality, with 14,270 women expected to die from the disease in 2014 [1]. Thus, there is an urgent need to develop novel treatments based on the distinct molecular background of ovarian cancer. The signaling cascade involving PI3K, AKT, and mTOR is the most frequently altered pathway in human cancer and controls many of the processes and characteristics that are important for cancer development, e.g., the cell cycle, cell survival, metabolism, motility, angiogenesis, chemoresistance, and genomic instability [3]. Previous studies have found that ovarian tumors often exhibit alterations in one or more components of the PI3K/AKT/mTOR signaling pathway, including mutations in the PIK3CA gene, which encodes the catalytic subunit of class I PI3K [4]; the PIK3R1 gene, which encodes the regulatory subunit of class I PI3K [5]; and the mTOR gene [6]. In addition, the activation of oncogenic tyrosine kinase receptors, loss of function of the tumor suppressors PTEN and inositol polyphosphate-4-phosphatase, type III (INPP4B) [7–9], and the mutation and/or amplification of the proto-oncogenes AKT1 and AKT2 [10,11] have also been detected in ovarian cancer. These molecular alterations, in addition to the druggability of the components of the PI3K/AKT/mTOR signaling cascade, suggest that targeting PI3K/AKT/mTOR signaling might represent a useful treatment strategy for ovarian cancer. In this article, we will review the recent progress in our understanding of the PI3K/AKT/mTOR pathway and summarize the novel therapeutic agents that target this pathway. Moreover, we will discuss how this pathway might best be targeted as treatments for ovarian cancer in light of ongoing preclinical and clinical trials. PI3K/AKT/mTOR signaling pathway As the major downstream effector of receptor tyrosine kinases (RTK) and G protein-coupled receptors, PI3K transduces signals from various
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growth factors and cytokines into intracellular messages by generating phospholipids, which activate downstream effectors including AKT and mTORC1 (Figs. 1 and 2). There are three class of PI3K (classes I–III). Class I PI3K includes class IA PI3K (PI3Kα, β, and δ), which are activated by receptors with protein tyrosine kinase activity, and class IB PI3K (PI3Kγ), which are activated by G protein-coupled receptors. Class IA PI3K are heterodimeric kinases consisting of a p85 regulatory subunit and a p110 catalytic subunit and are considered to play a more important role in cancer than other PI3K (Fig. 1). There are three class IA p110 isoforms (α, β, and γ), which are encoded by three genes (PIK3CA, PIK3CB, and PIK3CD, respectively). Of these, only PIK3CA is frequently mutated in human cancer [3]. In response to extracellular signals, activated PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2; PIP2) to generate phosphatidylinositol (3,4,5)-triphosphate (PI(3,4,5)P3; PIP3), leading to the recruitment of AKT to the plasma membrane, where it is phosphorylated and activated (Fig. 2). The tumor suppressors PTEN and INPP4B are the most important negative regulators of the PI3K signaling pathway. PTEN dephosphorylates the 3-position phosphate of PIP3 to produce PIP2, and INPP4B dephosphorylates the 4-position phosphate of phosphatidylinositol (3,4)-bisphosphate (PI(3,4)P2) to form PI(3)P, and both of these products inhibit PI3K-dependent AKT activation [9]. Thus, the loss of PTEN or INPP4B leads to the accumulation of PIP3 or PI(3,4)P2, respectively, resulting in the prolonged phosphorylation and activation of AKT. Activated AKT can directly activate mTORC1 by phosphorylating mTOR at Ser 2448 and can indirectly activate mTORC1 by phosphorylating tuberous sclerosis complex 2 (TSC2, also called tuberin). The phosphorylation of TSC2 by AKT leads to the inhibition of the function of the TSC1/TSC2 complex. When the TSC1/TSC2 complex is activated, TSC2 stimulates the conversion of Rheb (Ras homolog enriched in brain)-GTP to Rheb-GDP, which inactivates mTORC1. When TSC2 is inactivated (phosphorylated) by AKT, Rheb-GTP stimulates the activity of mTORC1. Therefore, genetic alterations that affect this signaling pathway lead to increased activation of mTORC1 [12,13]. Once activated, mTORC1 phosphorylates the translation-regulating factors ribosomal S6 kinase-1 (S6K-1) and eukaryote translation initiation factor 4E binding protein-1 (4EBP-1). The activation of S6K-1 leads to the translation of mRNA encoding ribosomal proteins, elongation factors, and other proteins required for transition from the G1 phase to S phase of the cell cycle. The phosphorylation of 4EBP-1 also enhances the translation of mRNA encoding cyclin D1, c-Myc, and hypoxiainducible factor-1α, leading to cell cycle progression or angiogenesis [12]. The other mTOR complex, mTORC2, consists of six proteins: mTOR, rictor (rapamycin-insensitive companion of mTOR), mSIN1 (mammalian stress-activated protein kinase-interacting protein), protor (protein observed with rictor), mLST8/GβL (G-protein β-subunit-like protein),
RTKs
PI(4,5)P2
p85 p110 Class IA PI3K
P
P
PI(3,4,5)P3
P P P AKT
0 0 0 0 0
PI(4,5)P2
P
P
p101
GPCRs
p110 Class IB PI3K
Fig. 1. Inputs from receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCR) to class I PI3K.
Please cite this article as: Mabuchi S, et al, The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer, Gynecol Oncol (2015), http:// dx.doi.org/10.1016/j.ygyno.2015.02.003
S. Mabuchi et al. / Gynecologic Oncology xxx (2015) xxx–xxx
3
RTKs
PI(4,5)P2
IRS-1
P
PI(3,4,5)P3
P
PTEN
PI3K
mLST8
mTOR Rictor
P
Thr308
mSin1 Ser473
AKT
Deptor
PRAS40
Raptor
4EBP-1
mTOR
mLST8
Protein translation
P
INPP4B
mTORC1 S6K1
PI(3)P
P
PDK1
mTORC2
protor
PI(3,4)P2
P P P
Rheb
TSC1
TSC2
Deptor
Cell growth, survival, angiogenesis
Fig. 2. Schematic representation of the PI3K/AKT/mTOR signaling pathway.
and DEPTOR (disheveled, egl-10, and pleckstrin domain-containing mTOR-interacting protein) [12,13]. The precise mechanism by which mTORC2 is activated remains unclear. However, a recent report suggested that PI3K is required to activate mTORC2 [14]. Activated mTORC2, in which mTOR is phosphorylated at Ser 2481 [13,15], in turn phosphorylates kinases, such as AKT, serum and glucocorticoidregulated kinases, and protein kinase C-α, and controls cell growth by regulating lipogenesis, glucose metabolism, the actin cytoskeleton, and apoptosis [12]. Alteration of the PI3K/AKT/mTOR pathway in ovarian cancer Various genetic alterations that induce increased PI3K/AKT/mTOR signaling have been found in ovarian cancer (Table 1). Levine et al. detected somatic activating mutations in the PIK3CA gene, which encodes the p110α catalytic subunit of PI3K, in 12% of ovarian tumors [4]. In addition, activating mutations in the PIK3R1 gene, which encodes the p85α regulatory subunit of PI3K, were found to be present in 3.8% of ovarian tumors [5], and somatic mutations in PTEN, AKT1, and mTOR were observed in 9.8% [7], 2% [11], and 1.9% [6] of ovarian tumors, respectively. Furthermore, AKT2 amplification was detected in 13.3% of primary ovarian tumors [10]. The activation of PTEN by hypermethylation
Table 1 Incidence of genetic alterations in PI3K/AKT/mTOR pathway in ovarian cancer. Gene
Genetic alteration
Cancer type
Incidence of alterations
PTEN INPP4B
Mutation Loss of heterozygosity Mutation Mutation
Ovarian cancer Ovarian cancer
9.8% 39.8%
Ovarian cancer Ovarian Clear Cell Carcinoma Ovarian cancer Ovarian cancer Ovarian cancer Ovarian cancer
12% 46%
4 18
3.8% 2% 13.3% 1.9%
5 11 10 6
PIK3CA
PIK3R1 AKT1 AKT2 mTOR
Mutation Mutation Amplification Mutation
of the PTEN promoter or loss of heterozygosity at the INPP4B locus has also been observed in 8.2% [8] and 39% of ovarian tumors [9], respectively. Any one of these upstream genetic or epigenetic changes can lead to the increased activation of PI3K/AKT/mTOR signaling in ovarian cancer. Recent studies including The Cancer Genome Atlas program have provided a more detailed understanding of the roles played by PI3K pathway aberrations in ovarian cancer. In high-grade serous ovarian carcinoma, the mutation of PIK3CA and AKT, or inactivating mutations in the PTEN gene are rare (b5%) [16]. However, immunohistochemical analyses of PI3K/AKT/mTOR have found that this pathway is activated in roughly half of high-grade serous ovarian carcinomas [17]. In contrast to high-grade serous ovarian cancers, genetic alterations are more common in ovarian clear cell carcinoma (OCCC) and endometrioid adenocarcinoma (EnOC). PIK3CA mutation with gain of function has been suggested to occur in 33–40% of OCCC and 12–20% of EnOC [18]. Furthermore, in a previous study AKT2 amplification was observed in 14% of OCCC cases [19]. In addition to these genetic alterations, the loss of PTEN expression has been detected in 40% of OCCC [20]. Consistent with these genetic alterations, our group examined tissue microarrays of 98 primary ovarian tumors [52 OCCC and 46 serous adenocarcinomas (SAC)] to tissue microarrays and demonstrated that AKT, mTORC1, and mTORC2 are more frequently activated in CCC than SAC (OCCC vs SAC for AKT, 69.2% vs. 63%; mTORC1, 86.6% vs. 50%; and mTORC2, 71.2% vs. 45.7%) [15,21,22]. Inhibitors of the PI3K/AKT/mTOR signaling pathway
References 7 8
PI3K/AKT/mTOR pathway inhibitors fall into 4 main categories: mTOR inhibitors, PI3K inhibitors, dual mTOR/PI3K inhibitors, and AKT inhibitors (Fig. 3). In addition, metformin can indirectly inhibit this pathway. Preclinically, inhibitors of PI3K [23], AKT [21], or mTOR [15, 22] have shown significant anti-tumor activities either as single agents or when used in combination with cytotoxic anti-cancer agents in preclinical in vitro and in vivo models of ovarian cancer. Importantly, PI3K/AKT/mTOR inhibitors had marked anti-tumor effects in ovarian cancer cells exhibiting high AKT/mTORC1 activity, but minimal effects in ovarian cancer cells displaying low AKT/mTORC1 activity [15,
Please cite this article as: Mabuchi S, et al, The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer, Gynecol Oncol (2015), http:// dx.doi.org/10.1016/j.ygyno.2015.02.003
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S. Mabuchi et al. / Gynecologic Oncology xxx (2015) xxx–xxx
PI3K inhibitors
PI3K
AKT inhibitors
AKT
mTORC1 inhibitors
mTORC1
Class I
Dual PI3K/mTOR inhibitors
mTORC2
mTORC 1/2 inhibitors
AKT inhibitors AKT inhibitors can be grouped into three classes including lipidbased phosphatidylinositol (PI) analogs, ATP-competitive inhibitors, and allosteric inhibitors. Perifosine, which is the most clinically studied AKT inhibitor, is a lipid-based PI analog that targets the pleckstrin homology domain of AKT, preventing its translocation to the cell membrane. Among the three classes of AKT inhibitors, allosteric AKT inhibitors display highly specific selectivity for AKT isoforms. Considering the genetic background of ovarian cancer, allosteric AKT inhibitors such as MK2206 that can target both AKT1 and AKT2 might be the best agents for treating ovarian cancer. In clinical trials, AKT inhibitors have shown similar toxicities to those caused by PI3K inhibitors, such as hyperglycemia, rashes, stomatitis, and gastrointestinal side effects [25].
Survival, Proliferation, Angiogenesis mTOR inhibitors Fig. 3. PI3K/AKT/mTOR inhibitors.
21–25]. Therefore, we consider that OCCC or EnOC, which often exhibit PI3K/AKT/mTOR activation, might be the most susceptible to PI3K/AKT/ mTOR inhibition-based therapies.
PI3K inhibitors Pan-class I PI3K inhibitors Pan-class I PI3K inhibitors can inhibit the kinase activity of all 4 isoforms of class I PI3K. The main advantage of pan-class I PI3K inhibitors is that most cancer cells express multiple PI3K isoforms with redundant oncogenic signaling functions. Early clinical trials have suggested that the most common toxicities of pan-class I PI3K inhibitors are hyperglycemia, skin toxicities, stomatitis, and gastrointestinal side effects. Of these, hyperglycemia is likely to be a mechanism-based toxicity given the well described role of PI3K in insulin receptor signaling [3,25].
Isoform-selective PI3K inhibitors This class of agents target the specific PI3K p110 isoforms involved in particular types of cancer. The p110α isoform (which is encoded by the PIK3CA gene) is a frequent genetic driver (PIK3CA mutations) of ovarian cancer, whereas p110β activity is known to be essential in cancer cells lacking PTEN. As for the p110δ isoform, it plays a fundamental role in the survival of normal B cells and is implicated in malignancies affecting this lineage. Thus, the main theoretical advantage of these inhibitors is that they have the potential to completely block the relevant target whilst causing limited toxicities compared with pan-PI3K inhibitors. Consistent with these findings, preclinical studies have detected significant activities of PI3Kα inhibitor in tumors exhibiting PIK3CA mutations, PI3Kβ inhibitors in tumors with PTEN loss, and PI3Kδ inhibitors in hematologic malignancies. In addition, PI3Kδ inhibitors have already shown very promising activity in patients with chronic lymphocytic leukemia [26].
Rapamycin and its analogs Rapamycin (sirolimus), a potent inhibitor of mTORC1, was first isolated in 1975 from the bacterium Streptomyces hygroscopicus. Rapamycin inhibits mTORC1 by first binding to the intracellular protein FK506 binding protein 12 (FKBP12). The resultant rapamycin–FKBP12 complex then binds to the FKBP12–rapamycin-binding domain (FRB) of mTORC1 and inhibits the serine/threonine kinase activity of mTORC1 via an allosteric mechanism. In contrast to mTORC1, the rapamycin–FKBP12 complex cannot interact with the FRB domain of mTORC2, and thus, mTORC2 is generally resistant to rapamycin treatment [12]. As rapamycin displays very poor water solubility, which limits its clinical use, several soluble ester analogs of rapamycin (rapalogs) have been developed [12]. Currently, these analogs include temsirolimus, everolimus, and ridaforolimus. Temsirolimus and everolimus are formulated for intravenous and oral administration, respectively. Ridaforolimus was initially developed as an intravenous formulation, but an oral formulation was subsequently produced [12,28]. Clinically, rapalogs are generally well tolerated, with the most common side effects including stomatitis, rashes, fatigue, hyperglycemia, hyperlipidemia, hypercholesterolemia, and myelosuppression [3,12,25].
ATP-competitive inhibitors Different from rapalogs, ATP-competitive inhibitors do not require co-factors such as FKBP12 to bind to mTOR. By competing with ATP for the ATP-binding sites of mTOR, this class of mTOR inhibitors can inhibit the kinase activity of both mTORC1 and mTORC2. Although there is a concern that the simultaneous inhibition of mTORC1 and mTORC2 might result in greater toxicities in normal tissues, ATP-competitive mTOR inhibitors have been shown to display stronger anti-proliferative activity than rapalogs across a broad range of cancers including ovarian cancer [12,15].
Metformin Dual PI3K/mTOR inhibitors Structural similarities between the ATP-binding domain of p110 and the catalytic domain of mTOR have led to the development of a class of agents that inhibit both class I PI3K and mTORC1/2. Theoretically, dual mTOR/PI3K inhibitors should lead to more complete suppression of the PI3K/AKT/mTOR pathway than targeting either component independently. In agreement with this, in preclinical studies of ovarian cancer dual PI3K/mTOR inhibitors were found to exhibit greater in vitro and in vivo anti-tumor activity than mTOR inhibitors alone [27]. The safety profile of these inhibitors is similar to that of pan-PI3K inhibitors, with common adverse events including nausea, diarrhea, fatigue, and vomiting [3,25].
Metformin, the most commonly prescribed oral anti-diabetic agent, has been shown to reduce the incidence of malignancies in patients with diabetes. The activation of 5′ adenosine monophosphateactivated protein kinase (AMPK) by metformin plays an important role in mediating the drug's effects. AMPK activation results in the phosphorylation and activation of TSC2, which exerts inhibitory effects on mTORC1. Metformin-induced AMPK activation also reduces AKT activity by inhibiting insulin receptor substrate 1 (IRS-1). Ultimately, AMPK activation results in the inhibition of the PI3K/AKT/mTOR signaling pathway, making metformin an effective treatment for cancer [28].
Please cite this article as: Mabuchi S, et al, The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer, Gynecol Oncol (2015), http:// dx.doi.org/10.1016/j.ygyno.2015.02.003
S. Mabuchi et al. / Gynecologic Oncology xxx (2015) xxx–xxx
5
Table 2 Summary of PI3K/AKT inhibitors in clinical trials. Targets
Compound
ClinicalTrials.gov Identifier
Eligibility
Condition
Interventions
Phase
PI3K
BKM120
NCT01623349
Recurrent
BKM120 plus Olaparib
Phase I
PI3K/mTOR
SAR245409
NCT01936363
Ovarian cancer Breast cancer Ovarian Cancer
Unresectable
Randomized phase II
Gynecologic malignancies including ovarian cancer Ovarian cancer Fallopian tube cancer Primary peritoneal cancer Ovarian cancer Ovarian cancer Fallopian tube cancer Primary peritoneal cancer Ovarian cancer Fallopian tube cancer Primary peritoneal cancer Endometrial cancer Breast cancer Ovarian cancer Fallopian tube cancer Primary peritoneal cancer
Recurrent or advanced Recurrent
➢Pimasertib plus SAR245409 ➢Pimasertib plus Placebo Perifosine MK2206
Phase II
GSK2141795 GSK2110183 plus carboplatin/paclitaxel ➢AZD5363 plus Olaparib ➢AZD2014 (mTROC1/2 inhibitor) plus Olaparib Triciribine plus Carboplatin
Phase I Phase I/II
a
AKT
Perifosine
NA
AKT
MK2206
NCT01283035
AKT AKT
GSK2141795 GSK2110183
NCT01266954 NCT01653912
AKT
AZD5363
NCT02208375
AKT
Triciribine
NCT01690468
Recurrent Recurrent Recurrent
Recurrent
Phase II
Phase I/II
Phase I/II
NA, not available. a This study is currently being conducted by Yakult Honsha Co., Ltd.
Clinical trials of PI3K/AKT/mTOR inhibitors in ovarian cancer On the basis of promising preclinical findings, PI3K/AKT/mTOR inhibitors have been evaluated in clinical trials. Tables 2 and 3 list the compounds that are currently being examined in clinical trials involving ovarian cancer patients. So far, only a phase I trial of an AKT inhibitor [29] and a phase II trial of an mTORC1 inhibitor [30] have published results. Phase I trial of an AKT inhibitor A phase I trial designed to evaluate the toxicities and the efficacy of combination treatment involving perifosine and docetaxel against recurrent ovarian cancer was conducted [29]. Although perifosine did not demonstrate satisfactory efficacy in this study, treatment with perifosine plus docetaxel appeared to be more effective in cases in which the PI3K/AKT pathway was mutationally activated [29], indicating that the clinical development of AKT inhibitors requires appropriate patient selection based on reliable biomarkers. With this in mind, Yakult
Honsha Co., Ltd. is currently conducting a phase II clinical trial of perifosine in Japan to investigate its efficacy, as well as the relationship between PIK3CA status and the response to treatment, in patients with recurrent gynecological malignancies including ovarian cancer. Phase II trial of an mTORC1 inhibitor In a GOG phase II trial (GOG 170-I), temsirolimus monotherapy was evaluated in patients with persistent or recurrent epithelial ovarian or primary peritoneal malignancies [30]. Of the 60 enrolled patients, 54 were eligible for evaluation. Among these patients, 9.3% achieved partial responses, and 24.1% exhibited progression-free survival (PFS) of ≥6 months, which was just below the level required to warrant inclusion in a phase III study involving unselected patients [30]. In this study, the patients whose ovarian tumors exhibited mTORC1 activity demonstrated a higher response rate than those whose tumors did not display mTORC1 activity (PFS: ≥6 month rate, 30.3% vs. 11.8%; response rate: 11.8% vs. 5.9%). Based on this result, a clinical study specifically targeting OCCC, which often exhibits PI3K/AKT/mTOR activation,
Table 3 Summary of mTOR inhibitors in clinical trials. Targets
Compound
ClinicalTrials.gov Identifier
Eligibility
Condition
Interventions
Phase
mTORC1
Temsirolimus
NCT01196429
Clear cell ovarian cancer
Temsirolimus
NCT01460979
mTORC1
Temsirolimus
NCT00982631
Recurrent or advanced
Temsirolimus plus PLD
Phase I
mTORC1
Temsirolimus
NCT01065662
Recurrent
Temsirolimus plus cediranib
Phase I
mTORC1
Everolimus
NCT01031381
Recurrent
Everolimus plus bevacizumab
Phase II
mTORC1
Everolimus
NCT00886691
Recurrent
mTORC1 mTORC1
Everolimus Everolimus
NCT02188550 NCT01281514
➢Bevacizumab ➢Bevacizumab plus everolimus Everolimus plus letrozole Everolimus plus carboplatin/PLD
Randomized phase II Phase II Phase I
mTORC1
Ridaforolimus
NCT01256268
Ovarian cancer Endometrial cancer Ovarian cancer Breast cancer Endometrial cancer Gynecologic malignancies including ovarian cancer Ovarian cancer Fallopian tube cancer Primary peritoneal cancer Ovarian cancer Fallopian Tube Cancer Primary Peritoneal Cancer Ovarian cancer Endometrial cancer Ovarian cancer Fallopian tube cancer Primary Peritoneal cancer Ovarian cancer Endometrial cancer
Temsirolimus plus carboplatin/paclitaxel flowed by temsirolimus consolidation Temsirolimus
Phase II
mTORC1
Front-line therapy Recurrent
Ridaforolimus plus carboplatin/paclitaxel
Phase I
mTORC1/2 mTORC1/2
AZD2014 AZD2014
NCT02193633 NCT02208375
AZD2014 plus paclitaxel 1. AZD5363 plus Olaparib 2. AZD2014 (mTROC1/2 inhibitor) plus Olaparib
Phase I Phase I/II
Ovarian Cancer Ovarian cancer Fallopian Tube Cancer Primary Peritoneal cancer Endometrial cancer Breast cancer
Recurrent Recurrent Recurrent or advanced Recurrent Recurrent
Phase II
NA, not available; PLD, pegylated liposomal doxorubicin hydrochloride.
Please cite this article as: Mabuchi S, et al, The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer, Gynecol Oncol (2015), http:// dx.doi.org/10.1016/j.ygyno.2015.02.003
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S. Mabuchi et al. / Gynecologic Oncology xxx (2015) xxx–xxx
is currently being conducted by the Gynecologic Oncology Group (GOG). This study is a phase II trial (protocol GOG0268), which is examining temsirolimus in combination with carboplatin and paclitaxel followed by temsirolimus consolidation as a first-line therapy for patients with stage III–IV OCCC. Resistance to PI3K/AKT/mTOR inhibitors The precise mechanism responsible for resistance to PI3K/AKT/ mTOR inhibitors remains largely unknown. However, recent investigations of mTORC1 inhibitors have suggested that it involves the loss of the negative feedback loops that are normally induced when the PI3K/ AKT/mTOR pathway is active. The first of these negative feedback loops is the mTORC2-independent IRS-1-dependent activation of AKT in response to mTORC1 inhibition [31]. The second involves mTORC2mediated AKT activation in response to treatment with mTORC1 inhibitors [15], and the third involves mTORC1 inhibition-mediated mitogenactivated protein kinase (MAPK) activation [32]. Thus, novel inhibitors that target both mTORC1 and mTORC2; or mTORC1, mTORC2, and PI3K; or combination treatments involving mTORC1-targeting agents and MAPK inhibitors might have the potential to overcome resistance to mTORC1 inhibitors. Finally, as it has been reported that rapalogs or ATP-competitive mTOR inhibitors increase RTK expression that results in PI3K-dependent AKT activation or Ras-dependent MAPK activation [33], combining PI3K/AKT/mTOR inhibitors with tyrosine kinase inhibiters (TKI) might have therapeutic advantages over the use of PI3K/AKT/mTOR inhibitors alone. Future directions Combining PI3K/AKT/mTOR inhibition with other targeted agents The early results from clinical trials involving advanced solid tumors are rather sobering [3,27]. The relatively modest single-agent activity of PI3K/AKT/mTOR inhibitors, especially when compared with that of agents targeting driver oncogenes such as BCR-ABL, BRAF, or anaplastic lymphoma kinase (ALK), indicates that oncogene addiction to PI3K/ AKT/mTOR signaling is not absolute in ovarian cancer. Thus, it is necessary to combine PI3K/AKT/mTOR inhibitors with other targeted agents in order to unleash their full potential as treatments for ovarian cancer. Greater clinical responses might be achieved by combining PI3K/ AKT/mTOR inhibitors with other targeted agents. Considering the potential resistance mechanisms mentioned above, combining PI3K/AKT/ mTOR inhibitors with TKI is worth investigating. As preclinical and clinical investigations have suggested that cancer cells that exhibit activating mutations in the KRAS gene are relatively resistant to PI3K/AKT/ mTOR inhibition [34], the combination of PI3K/AKT/mTOR inhibitors with drugs that target Ras/Raf/mitogen activated kinase kinase (MEK)/ extracellular-signal-regulated kinase signaling is another attractive strategy. In a preclinical investigation involving a KRAS-driven lung cancer model, an MEK inhibitor and the dual PI3K–mTOR inhibitor NPVBEZ235 demonstrated synergistic effects [35]. Another interesting combination is the use of PI3K inhibitors together with poly-ADP ribose polymerase (PARP) inhibitors. Preclinical investigations have demonstrated that PI3K inhibition is associated with the loss of homologous recombination repair capacity, increased DNA damage, and more sensitization of breast cancer cells to PARP inhibitors [36]. It has recently been suggested that PTEN is also involved in the maintenance of genomic stability and that the loss of PTEN function results in defective homologous recombination-mediated repair of DNA double-strand breaks. A phase I trial of combined treatment involving the PARP inhibitor olaparib and pan-PI3K inhibitors is currently enrolling patients with triple-negative breast cancer and high-grade serous ovarian cancer (Table 1). We consider that this combination is worth investigating in patients with OCCC, in which loss of PTEN expression is observed in 40% of cases [20].
Patient selection To develop clinically effective treatments, it is crucial to identify subgroups of patients that are most likely to benefit from PI3K/AKT/mTOR inhibition-based therapy using reliable biomarkers. Previous preclinical investigations have suggested that ovarian cancer cells exhibiting PIK3CA mutations, PTEN loss, the hyperactivation of AKT/mTORC1 signaling, or cyclin D1 overexpression are particularly sensitive to AKT/ mTORC1 inhibitors [37]. However, a recent preclinical investigation using 17 well-characterized ovarian cancer cell lines suggested that AKT activation was necessary but not sufficient to induce sensitivity to AKT inhibitors in ovarian cancer [34]. Despite the phosphorylation and activation of AKT, cancer cell lines with activating mutations in the KRAS gene or inactivating mutations in the retinoblastoma (RB) gene were found to be relatively resistant to AKT inhibition [34]. Consistent with this finding, a recent clinical report suggested that PI3K/AKT/ mTOR inhibition might be most effective against ovarian tumors that possess activating mutations in the PIK3CA gene, whilst activating mutations in the KRAS gene are likely to be a predictor of resistance [38]. The potential of these candidate biomarkers to predict the sensitivity of ovarian tumors to PI3K/AKT/mTOR inhibitors needs to be investigated in the prospective setting in future clinical trials. Potential as chemopreventive agents Recently, it has been demonstrated that PTEN and ARID1A double knockout mice developed ovarian endometrioid or undifferentiated carcinoma, whereas ARID1A knockout mice did not develop histological alterations [39], indicating that PI3K/AKT/mTOR inhibitors have potential as chemopreventive agents. As consistent with this, using TgMISIIR-TAg transgenic mice that develop ovarian cancer accompanied by ascites and peritoneal dissemination, our group demonstrated that mTORC1 inhibition by everolimus treatment markedly delayed tumor development and progression [40]. Thus, the potential of PI3K/AKT/ mTOR inhibitors to prevent or delay the onset of ovarian cancer might be worth investigating, especially in women who are at high risk of the disease. Conclusions The PI3K/AKT/mTOR signaling pathway is frequently activated in ovarian cancer. On the basis of promising preclinical findings, inhibitors targeting this pathway are currently being evaluated as treatment strategies for ovarian cancer, either monotherapy or in combination with cytotoxic agents. A greater focus on patient selection based on predictive biomarkers, a deeper understanding of the mechanisms responsible for resistance, and the identification of effective treatment combinations will maximize the potential of PI3K/AKT/mTOR inhibitors. Solving these problems will aid the development of optimal PI3K/AKT/mTORtargeting therapies for ovarian cancer. Conflicts of interest statement The authors declare that they have no conflicts of interest.
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Please cite this article as: Mabuchi S, et al, The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer, Gynecol Oncol (2015), http:// dx.doi.org/10.1016/j.ygyno.2015.02.003
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer Seiji Mabuchi ⁎, Hiromasa Kuroda, Ryoko Takahashi, Tomoyuki Sasano Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
H I G H L I G H T S • PI3K/AKT/mTOR pathway is frequently mutated or activated in ovarian cancer. • PI3K/AKT/mTOR pathway plays a crucial role in the progression of ovarian cancer. • P3K/AKTmTOR inhibition might be an effetive treatment for ovarian cancer.
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Article history: Received 17 December 2014 Accepted 2 February 2015 Available online xxxx Keywords: PI3K AKT mTOR mTORC1 mTORC2 Ovarian cancer
a b s t r a c t The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway plays a critical role in the malignant transformation of human tumors and their subsequent growth, proliferation, and metastasis. Preclinical investigations have suggested that the PI3K/AKT/mTOR pathway is frequently activated in ovarian cancer, especially in clear cell carcinoma and endometrioid adenocarcinoma. Thus, this pathway is regarded as an attractive candidate for therapeutic interventions, and inhibitors targeting different components of this pathway are in various stages of clinical development. Here, we highlight the recent progress that has been made in our understanding of the PI3K/AKT/mTOR pathway and discuss the potential of therapeutic agents that target this pathway as treatments for ovarian cancer and the obstacles to their development. © 2015 Elsevier Inc. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . PI3K/AKT/mTOR signaling pathway . . . . . . . . . . . . . . . . Alteration of the PI3K/AKT/mTOR pathway in ovarian cancer . . . . . Inhibitors of the PI3K/AKT/mTOR signaling pathway . . . . . . . . . PI3K inhibitors . . . . . . . . . . . . . . . . . . . . . . . Pan-class I PI3K inhibitors . . . . . . . . . . . . . . . Isoform-selective PI3K inhibitors . . . . . . . . . . . . Dual PI3K/mTOR inhibitors . . . . . . . . . . . . . . AKT inhibitors . . . . . . . . . . . . . . . . . . . . . . . mTOR inhibitors . . . . . . . . . . . . . . . . . . . . . . . Rapamycin and its analogs . . . . . . . . . . . . . . . ATP-competitive inhibitors . . . . . . . . . . . . . . . . . . Metformin . . . . . . . . . . . . . . . . . . . . . . . . . Clinical trials of PI3K/AKT/mTOR inhibitors in ovarian cancer . . . . . Phase I trial of an AKT inhibitor . . . . . . . . . . . . . . . . Phase II trial of an mTORC1 inhibitor . . . . . . . . . . . . . Resistance to PI3K/AKT/mTOR inhibitors . . . . . . . . . . . . . . Future directions . . . . . . . . . . . . . . . . . . . . . . . . . Combining PI3K/AKT/mTOR inhibition with other targeted agents
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Abbreviations: CCC, clear cell carcinoma; SAC, serous adenocarcinoma; mTOR, mammalian target of rapamycin; mTORC, mTOR complex; S6K-1, ribosomal S6 kinase-1; 4E-BP1, elF4E binding protein 1; PI3K, phosphatidylinositol 3-kinase; cisplatin, cis-diaminodichloroplatinum; PTEN, phosphatase and tensin homolog deleted on chromosome 10. ⁎ Corresponding author at: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Fax: +81 6 68 79 3359. E-mail address: [email protected] (S. Mabuchi).
http://dx.doi.org/10.1016/j.ygyno.2015.02.003 0090-8258/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Mabuchi S, et al, The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer, Gynecol Oncol (2015), http:// dx.doi.org/10.1016/j.ygyno.2015.02.003
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Patient selection . . . . . . . . . Potential as chemopreventive agents Conclusions . . . . . . . . . . . . . Conflicts of interest statement . . . . . References . . . . . . . . . . . . . .
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Introduction It is estimated that more than 225,500 women worldwide are diagnosed with ovarian cancer each year [1]. Ovarian cancer is a heterogeneous disease that can be categorized into various histological subtypes: high-grade serous, low-grade serous, clear cell, endometrioid, and mucinous adenocarcinoma. Each histological subtype is associated with a distinct clinical behavior and molecular pattern, but historically ovarian cancer has been treated with a single entity. The current standard treatment for newly diagnosed ovarian cancer is a combination of cytoreductive surgery and platinum-based combination chemotherapy [2]. Despite recent advances, as more than two-thirds of ovarian cancer cases are diagnosed at an advanced stage ovarian cancer patients are still at significant risk of recurrence, which cure is generally difficult with current standard treatments [2]. As a result, ovarian cancer remains a leading cause of gynecological cancer mortality, with 14,270 women expected to die from the disease in 2014 [1]. Thus, there is an urgent need to develop novel treatments based on the distinct molecular background of ovarian cancer. The signaling cascade involving PI3K, AKT, and mTOR is the most frequently altered pathway in human cancer and controls many of the processes and characteristics that are important for cancer development, e.g., the cell cycle, cell survival, metabolism, motility, angiogenesis, chemoresistance, and genomic instability [3]. Previous studies have found that ovarian tumors often exhibit alterations in one or more components of the PI3K/AKT/mTOR signaling pathway, including mutations in the PIK3CA gene, which encodes the catalytic subunit of class I PI3K [4]; the PIK3R1 gene, which encodes the regulatory subunit of class I PI3K [5]; and the mTOR gene [6]. In addition, the activation of oncogenic tyrosine kinase receptors, loss of function of the tumor suppressors PTEN and inositol polyphosphate-4-phosphatase, type III (INPP4B) [7–9], and the mutation and/or amplification of the proto-oncogenes AKT1 and AKT2 [10,11] have also been detected in ovarian cancer. These molecular alterations, in addition to the druggability of the components of the PI3K/AKT/mTOR signaling cascade, suggest that targeting PI3K/AKT/mTOR signaling might represent a useful treatment strategy for ovarian cancer. In this article, we will review the recent progress in our understanding of the PI3K/AKT/mTOR pathway and summarize the novel therapeutic agents that target this pathway. Moreover, we will discuss how this pathway might best be targeted as treatments for ovarian cancer in light of ongoing preclinical and clinical trials. PI3K/AKT/mTOR signaling pathway As the major downstream effector of receptor tyrosine kinases (RTK) and G protein-coupled receptors, PI3K transduces signals from various
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growth factors and cytokines into intracellular messages by generating phospholipids, which activate downstream effectors including AKT and mTORC1 (Figs. 1 and 2). There are three class of PI3K (classes I–III). Class I PI3K includes class IA PI3K (PI3Kα, β, and δ), which are activated by receptors with protein tyrosine kinase activity, and class IB PI3K (PI3Kγ), which are activated by G protein-coupled receptors. Class IA PI3K are heterodimeric kinases consisting of a p85 regulatory subunit and a p110 catalytic subunit and are considered to play a more important role in cancer than other PI3K (Fig. 1). There are three class IA p110 isoforms (α, β, and γ), which are encoded by three genes (PIK3CA, PIK3CB, and PIK3CD, respectively). Of these, only PIK3CA is frequently mutated in human cancer [3]. In response to extracellular signals, activated PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2; PIP2) to generate phosphatidylinositol (3,4,5)-triphosphate (PI(3,4,5)P3; PIP3), leading to the recruitment of AKT to the plasma membrane, where it is phosphorylated and activated (Fig. 2). The tumor suppressors PTEN and INPP4B are the most important negative regulators of the PI3K signaling pathway. PTEN dephosphorylates the 3-position phosphate of PIP3 to produce PIP2, and INPP4B dephosphorylates the 4-position phosphate of phosphatidylinositol (3,4)-bisphosphate (PI(3,4)P2) to form PI(3)P, and both of these products inhibit PI3K-dependent AKT activation [9]. Thus, the loss of PTEN or INPP4B leads to the accumulation of PIP3 or PI(3,4)P2, respectively, resulting in the prolonged phosphorylation and activation of AKT. Activated AKT can directly activate mTORC1 by phosphorylating mTOR at Ser 2448 and can indirectly activate mTORC1 by phosphorylating tuberous sclerosis complex 2 (TSC2, also called tuberin). The phosphorylation of TSC2 by AKT leads to the inhibition of the function of the TSC1/TSC2 complex. When the TSC1/TSC2 complex is activated, TSC2 stimulates the conversion of Rheb (Ras homolog enriched in brain)-GTP to Rheb-GDP, which inactivates mTORC1. When TSC2 is inactivated (phosphorylated) by AKT, Rheb-GTP stimulates the activity of mTORC1. Therefore, genetic alterations that affect this signaling pathway lead to increased activation of mTORC1 [12,13]. Once activated, mTORC1 phosphorylates the translation-regulating factors ribosomal S6 kinase-1 (S6K-1) and eukaryote translation initiation factor 4E binding protein-1 (4EBP-1). The activation of S6K-1 leads to the translation of mRNA encoding ribosomal proteins, elongation factors, and other proteins required for transition from the G1 phase to S phase of the cell cycle. The phosphorylation of 4EBP-1 also enhances the translation of mRNA encoding cyclin D1, c-Myc, and hypoxiainducible factor-1α, leading to cell cycle progression or angiogenesis [12]. The other mTOR complex, mTORC2, consists of six proteins: mTOR, rictor (rapamycin-insensitive companion of mTOR), mSIN1 (mammalian stress-activated protein kinase-interacting protein), protor (protein observed with rictor), mLST8/GβL (G-protein β-subunit-like protein),
RTKs
PI(4,5)P2
p85 p110 Class IA PI3K
P
P
PI(3,4,5)P3
P P P AKT
0 0 0 0 0
PI(4,5)P2
P
P
p101
GPCRs
p110 Class IB PI3K
Fig. 1. Inputs from receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCR) to class I PI3K.
Please cite this article as: Mabuchi S, et al, The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer, Gynecol Oncol (2015), http:// dx.doi.org/10.1016/j.ygyno.2015.02.003
S. Mabuchi et al. / Gynecologic Oncology xxx (2015) xxx–xxx
3
RTKs
PI(4,5)P2
IRS-1
P
PI(3,4,5)P3
P
PTEN
PI3K
mLST8
mTOR Rictor
P
Thr308
mSin1 Ser473
AKT
Deptor
PRAS40
Raptor
4EBP-1
mTOR
mLST8
Protein translation
P
INPP4B
mTORC1 S6K1
PI(3)P
P
PDK1
mTORC2
protor
PI(3,4)P2
P P P
Rheb
TSC1
TSC2
Deptor
Cell growth, survival, angiogenesis
Fig. 2. Schematic representation of the PI3K/AKT/mTOR signaling pathway.
and DEPTOR (disheveled, egl-10, and pleckstrin domain-containing mTOR-interacting protein) [12,13]. The precise mechanism by which mTORC2 is activated remains unclear. However, a recent report suggested that PI3K is required to activate mTORC2 [14]. Activated mTORC2, in which mTOR is phosphorylated at Ser 2481 [13,15], in turn phosphorylates kinases, such as AKT, serum and glucocorticoidregulated kinases, and protein kinase C-α, and controls cell growth by regulating lipogenesis, glucose metabolism, the actin cytoskeleton, and apoptosis [12]. Alteration of the PI3K/AKT/mTOR pathway in ovarian cancer Various genetic alterations that induce increased PI3K/AKT/mTOR signaling have been found in ovarian cancer (Table 1). Levine et al. detected somatic activating mutations in the PIK3CA gene, which encodes the p110α catalytic subunit of PI3K, in 12% of ovarian tumors [4]. In addition, activating mutations in the PIK3R1 gene, which encodes the p85α regulatory subunit of PI3K, were found to be present in 3.8% of ovarian tumors [5], and somatic mutations in PTEN, AKT1, and mTOR were observed in 9.8% [7], 2% [11], and 1.9% [6] of ovarian tumors, respectively. Furthermore, AKT2 amplification was detected in 13.3% of primary ovarian tumors [10]. The activation of PTEN by hypermethylation
Table 1 Incidence of genetic alterations in PI3K/AKT/mTOR pathway in ovarian cancer. Gene
Genetic alteration
Cancer type
Incidence of alterations
PTEN INPP4B
Mutation Loss of heterozygosity Mutation Mutation
Ovarian cancer Ovarian cancer
9.8% 39.8%
Ovarian cancer Ovarian Clear Cell Carcinoma Ovarian cancer Ovarian cancer Ovarian cancer Ovarian cancer
12% 46%
4 18
3.8% 2% 13.3% 1.9%
5 11 10 6
PIK3CA
PIK3R1 AKT1 AKT2 mTOR
Mutation Mutation Amplification Mutation
of the PTEN promoter or loss of heterozygosity at the INPP4B locus has also been observed in 8.2% [8] and 39% of ovarian tumors [9], respectively. Any one of these upstream genetic or epigenetic changes can lead to the increased activation of PI3K/AKT/mTOR signaling in ovarian cancer. Recent studies including The Cancer Genome Atlas program have provided a more detailed understanding of the roles played by PI3K pathway aberrations in ovarian cancer. In high-grade serous ovarian carcinoma, the mutation of PIK3CA and AKT, or inactivating mutations in the PTEN gene are rare (b5%) [16]. However, immunohistochemical analyses of PI3K/AKT/mTOR have found that this pathway is activated in roughly half of high-grade serous ovarian carcinomas [17]. In contrast to high-grade serous ovarian cancers, genetic alterations are more common in ovarian clear cell carcinoma (OCCC) and endometrioid adenocarcinoma (EnOC). PIK3CA mutation with gain of function has been suggested to occur in 33–40% of OCCC and 12–20% of EnOC [18]. Furthermore, in a previous study AKT2 amplification was observed in 14% of OCCC cases [19]. In addition to these genetic alterations, the loss of PTEN expression has been detected in 40% of OCCC [20]. Consistent with these genetic alterations, our group examined tissue microarrays of 98 primary ovarian tumors [52 OCCC and 46 serous adenocarcinomas (SAC)] to tissue microarrays and demonstrated that AKT, mTORC1, and mTORC2 are more frequently activated in CCC than SAC (OCCC vs SAC for AKT, 69.2% vs. 63%; mTORC1, 86.6% vs. 50%; and mTORC2, 71.2% vs. 45.7%) [15,21,22]. Inhibitors of the PI3K/AKT/mTOR signaling pathway
References 7 8
PI3K/AKT/mTOR pathway inhibitors fall into 4 main categories: mTOR inhibitors, PI3K inhibitors, dual mTOR/PI3K inhibitors, and AKT inhibitors (Fig. 3). In addition, metformin can indirectly inhibit this pathway. Preclinically, inhibitors of PI3K [23], AKT [21], or mTOR [15, 22] have shown significant anti-tumor activities either as single agents or when used in combination with cytotoxic anti-cancer agents in preclinical in vitro and in vivo models of ovarian cancer. Importantly, PI3K/AKT/mTOR inhibitors had marked anti-tumor effects in ovarian cancer cells exhibiting high AKT/mTORC1 activity, but minimal effects in ovarian cancer cells displaying low AKT/mTORC1 activity [15,
Please cite this article as: Mabuchi S, et al, The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer, Gynecol Oncol (2015), http:// dx.doi.org/10.1016/j.ygyno.2015.02.003
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S. Mabuchi et al. / Gynecologic Oncology xxx (2015) xxx–xxx
PI3K inhibitors
PI3K
AKT inhibitors
AKT
mTORC1 inhibitors
mTORC1
Class I
Dual PI3K/mTOR inhibitors
mTORC2
mTORC 1/2 inhibitors
AKT inhibitors AKT inhibitors can be grouped into three classes including lipidbased phosphatidylinositol (PI) analogs, ATP-competitive inhibitors, and allosteric inhibitors. Perifosine, which is the most clinically studied AKT inhibitor, is a lipid-based PI analog that targets the pleckstrin homology domain of AKT, preventing its translocation to the cell membrane. Among the three classes of AKT inhibitors, allosteric AKT inhibitors display highly specific selectivity for AKT isoforms. Considering the genetic background of ovarian cancer, allosteric AKT inhibitors such as MK2206 that can target both AKT1 and AKT2 might be the best agents for treating ovarian cancer. In clinical trials, AKT inhibitors have shown similar toxicities to those caused by PI3K inhibitors, such as hyperglycemia, rashes, stomatitis, and gastrointestinal side effects [25].
Survival, Proliferation, Angiogenesis mTOR inhibitors Fig. 3. PI3K/AKT/mTOR inhibitors.
21–25]. Therefore, we consider that OCCC or EnOC, which often exhibit PI3K/AKT/mTOR activation, might be the most susceptible to PI3K/AKT/ mTOR inhibition-based therapies.
PI3K inhibitors Pan-class I PI3K inhibitors Pan-class I PI3K inhibitors can inhibit the kinase activity of all 4 isoforms of class I PI3K. The main advantage of pan-class I PI3K inhibitors is that most cancer cells express multiple PI3K isoforms with redundant oncogenic signaling functions. Early clinical trials have suggested that the most common toxicities of pan-class I PI3K inhibitors are hyperglycemia, skin toxicities, stomatitis, and gastrointestinal side effects. Of these, hyperglycemia is likely to be a mechanism-based toxicity given the well described role of PI3K in insulin receptor signaling [3,25].
Isoform-selective PI3K inhibitors This class of agents target the specific PI3K p110 isoforms involved in particular types of cancer. The p110α isoform (which is encoded by the PIK3CA gene) is a frequent genetic driver (PIK3CA mutations) of ovarian cancer, whereas p110β activity is known to be essential in cancer cells lacking PTEN. As for the p110δ isoform, it plays a fundamental role in the survival of normal B cells and is implicated in malignancies affecting this lineage. Thus, the main theoretical advantage of these inhibitors is that they have the potential to completely block the relevant target whilst causing limited toxicities compared with pan-PI3K inhibitors. Consistent with these findings, preclinical studies have detected significant activities of PI3Kα inhibitor in tumors exhibiting PIK3CA mutations, PI3Kβ inhibitors in tumors with PTEN loss, and PI3Kδ inhibitors in hematologic malignancies. In addition, PI3Kδ inhibitors have already shown very promising activity in patients with chronic lymphocytic leukemia [26].
Rapamycin and its analogs Rapamycin (sirolimus), a potent inhibitor of mTORC1, was first isolated in 1975 from the bacterium Streptomyces hygroscopicus. Rapamycin inhibits mTORC1 by first binding to the intracellular protein FK506 binding protein 12 (FKBP12). The resultant rapamycin–FKBP12 complex then binds to the FKBP12–rapamycin-binding domain (FRB) of mTORC1 and inhibits the serine/threonine kinase activity of mTORC1 via an allosteric mechanism. In contrast to mTORC1, the rapamycin–FKBP12 complex cannot interact with the FRB domain of mTORC2, and thus, mTORC2 is generally resistant to rapamycin treatment [12]. As rapamycin displays very poor water solubility, which limits its clinical use, several soluble ester analogs of rapamycin (rapalogs) have been developed [12]. Currently, these analogs include temsirolimus, everolimus, and ridaforolimus. Temsirolimus and everolimus are formulated for intravenous and oral administration, respectively. Ridaforolimus was initially developed as an intravenous formulation, but an oral formulation was subsequently produced [12,28]. Clinically, rapalogs are generally well tolerated, with the most common side effects including stomatitis, rashes, fatigue, hyperglycemia, hyperlipidemia, hypercholesterolemia, and myelosuppression [3,12,25].
ATP-competitive inhibitors Different from rapalogs, ATP-competitive inhibitors do not require co-factors such as FKBP12 to bind to mTOR. By competing with ATP for the ATP-binding sites of mTOR, this class of mTOR inhibitors can inhibit the kinase activity of both mTORC1 and mTORC2. Although there is a concern that the simultaneous inhibition of mTORC1 and mTORC2 might result in greater toxicities in normal tissues, ATP-competitive mTOR inhibitors have been shown to display stronger anti-proliferative activity than rapalogs across a broad range of cancers including ovarian cancer [12,15].
Metformin Dual PI3K/mTOR inhibitors Structural similarities between the ATP-binding domain of p110 and the catalytic domain of mTOR have led to the development of a class of agents that inhibit both class I PI3K and mTORC1/2. Theoretically, dual mTOR/PI3K inhibitors should lead to more complete suppression of the PI3K/AKT/mTOR pathway than targeting either component independently. In agreement with this, in preclinical studies of ovarian cancer dual PI3K/mTOR inhibitors were found to exhibit greater in vitro and in vivo anti-tumor activity than mTOR inhibitors alone [27]. The safety profile of these inhibitors is similar to that of pan-PI3K inhibitors, with common adverse events including nausea, diarrhea, fatigue, and vomiting [3,25].
Metformin, the most commonly prescribed oral anti-diabetic agent, has been shown to reduce the incidence of malignancies in patients with diabetes. The activation of 5′ adenosine monophosphateactivated protein kinase (AMPK) by metformin plays an important role in mediating the drug's effects. AMPK activation results in the phosphorylation and activation of TSC2, which exerts inhibitory effects on mTORC1. Metformin-induced AMPK activation also reduces AKT activity by inhibiting insulin receptor substrate 1 (IRS-1). Ultimately, AMPK activation results in the inhibition of the PI3K/AKT/mTOR signaling pathway, making metformin an effective treatment for cancer [28].
Please cite this article as: Mabuchi S, et al, The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer, Gynecol Oncol (2015), http:// dx.doi.org/10.1016/j.ygyno.2015.02.003
S. Mabuchi et al. / Gynecologic Oncology xxx (2015) xxx–xxx
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Table 2 Summary of PI3K/AKT inhibitors in clinical trials. Targets
Compound
ClinicalTrials.gov Identifier
Eligibility
Condition
Interventions
Phase
PI3K
BKM120
NCT01623349
Recurrent
BKM120 plus Olaparib
Phase I
PI3K/mTOR
SAR245409
NCT01936363
Ovarian cancer Breast cancer Ovarian Cancer
Unresectable
Randomized phase II
Gynecologic malignancies including ovarian cancer Ovarian cancer Fallopian tube cancer Primary peritoneal cancer Ovarian cancer Ovarian cancer Fallopian tube cancer Primary peritoneal cancer Ovarian cancer Fallopian tube cancer Primary peritoneal cancer Endometrial cancer Breast cancer Ovarian cancer Fallopian tube cancer Primary peritoneal cancer
Recurrent or advanced Recurrent
➢Pimasertib plus SAR245409 ➢Pimasertib plus Placebo Perifosine MK2206
Phase II
GSK2141795 GSK2110183 plus carboplatin/paclitaxel ➢AZD5363 plus Olaparib ➢AZD2014 (mTROC1/2 inhibitor) plus Olaparib Triciribine plus Carboplatin
Phase I Phase I/II
a
AKT
Perifosine
NA
AKT
MK2206
NCT01283035
AKT AKT
GSK2141795 GSK2110183
NCT01266954 NCT01653912
AKT
AZD5363
NCT02208375
AKT
Triciribine
NCT01690468
Recurrent Recurrent Recurrent
Recurrent
Phase II
Phase I/II
Phase I/II
NA, not available. a This study is currently being conducted by Yakult Honsha Co., Ltd.
Clinical trials of PI3K/AKT/mTOR inhibitors in ovarian cancer On the basis of promising preclinical findings, PI3K/AKT/mTOR inhibitors have been evaluated in clinical trials. Tables 2 and 3 list the compounds that are currently being examined in clinical trials involving ovarian cancer patients. So far, only a phase I trial of an AKT inhibitor [29] and a phase II trial of an mTORC1 inhibitor [30] have published results. Phase I trial of an AKT inhibitor A phase I trial designed to evaluate the toxicities and the efficacy of combination treatment involving perifosine and docetaxel against recurrent ovarian cancer was conducted [29]. Although perifosine did not demonstrate satisfactory efficacy in this study, treatment with perifosine plus docetaxel appeared to be more effective in cases in which the PI3K/AKT pathway was mutationally activated [29], indicating that the clinical development of AKT inhibitors requires appropriate patient selection based on reliable biomarkers. With this in mind, Yakult
Honsha Co., Ltd. is currently conducting a phase II clinical trial of perifosine in Japan to investigate its efficacy, as well as the relationship between PIK3CA status and the response to treatment, in patients with recurrent gynecological malignancies including ovarian cancer. Phase II trial of an mTORC1 inhibitor In a GOG phase II trial (GOG 170-I), temsirolimus monotherapy was evaluated in patients with persistent or recurrent epithelial ovarian or primary peritoneal malignancies [30]. Of the 60 enrolled patients, 54 were eligible for evaluation. Among these patients, 9.3% achieved partial responses, and 24.1% exhibited progression-free survival (PFS) of ≥6 months, which was just below the level required to warrant inclusion in a phase III study involving unselected patients [30]. In this study, the patients whose ovarian tumors exhibited mTORC1 activity demonstrated a higher response rate than those whose tumors did not display mTORC1 activity (PFS: ≥6 month rate, 30.3% vs. 11.8%; response rate: 11.8% vs. 5.9%). Based on this result, a clinical study specifically targeting OCCC, which often exhibits PI3K/AKT/mTOR activation,
Table 3 Summary of mTOR inhibitors in clinical trials. Targets
Compound
ClinicalTrials.gov Identifier
Eligibility
Condition
Interventions
Phase
mTORC1
Temsirolimus
NCT01196429
Clear cell ovarian cancer
Temsirolimus
NCT01460979
mTORC1
Temsirolimus
NCT00982631
Recurrent or advanced
Temsirolimus plus PLD
Phase I
mTORC1
Temsirolimus
NCT01065662
Recurrent
Temsirolimus plus cediranib
Phase I
mTORC1
Everolimus
NCT01031381
Recurrent
Everolimus plus bevacizumab
Phase II
mTORC1
Everolimus
NCT00886691
Recurrent
mTORC1 mTORC1
Everolimus Everolimus
NCT02188550 NCT01281514
➢Bevacizumab ➢Bevacizumab plus everolimus Everolimus plus letrozole Everolimus plus carboplatin/PLD
Randomized phase II Phase II Phase I
mTORC1
Ridaforolimus
NCT01256268
Ovarian cancer Endometrial cancer Ovarian cancer Breast cancer Endometrial cancer Gynecologic malignancies including ovarian cancer Ovarian cancer Fallopian tube cancer Primary peritoneal cancer Ovarian cancer Fallopian Tube Cancer Primary Peritoneal Cancer Ovarian cancer Endometrial cancer Ovarian cancer Fallopian tube cancer Primary Peritoneal cancer Ovarian cancer Endometrial cancer
Temsirolimus plus carboplatin/paclitaxel flowed by temsirolimus consolidation Temsirolimus
Phase II
mTORC1
Front-line therapy Recurrent
Ridaforolimus plus carboplatin/paclitaxel
Phase I
mTORC1/2 mTORC1/2
AZD2014 AZD2014
NCT02193633 NCT02208375
AZD2014 plus paclitaxel 1. AZD5363 plus Olaparib 2. AZD2014 (mTROC1/2 inhibitor) plus Olaparib
Phase I Phase I/II
Ovarian Cancer Ovarian cancer Fallopian Tube Cancer Primary Peritoneal cancer Endometrial cancer Breast cancer
Recurrent Recurrent Recurrent or advanced Recurrent Recurrent
Phase II
NA, not available; PLD, pegylated liposomal doxorubicin hydrochloride.
Please cite this article as: Mabuchi S, et al, The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer, Gynecol Oncol (2015), http:// dx.doi.org/10.1016/j.ygyno.2015.02.003
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is currently being conducted by the Gynecologic Oncology Group (GOG). This study is a phase II trial (protocol GOG0268), which is examining temsirolimus in combination with carboplatin and paclitaxel followed by temsirolimus consolidation as a first-line therapy for patients with stage III–IV OCCC. Resistance to PI3K/AKT/mTOR inhibitors The precise mechanism responsible for resistance to PI3K/AKT/ mTOR inhibitors remains largely unknown. However, recent investigations of mTORC1 inhibitors have suggested that it involves the loss of the negative feedback loops that are normally induced when the PI3K/ AKT/mTOR pathway is active. The first of these negative feedback loops is the mTORC2-independent IRS-1-dependent activation of AKT in response to mTORC1 inhibition [31]. The second involves mTORC2mediated AKT activation in response to treatment with mTORC1 inhibitors [15], and the third involves mTORC1 inhibition-mediated mitogenactivated protein kinase (MAPK) activation [32]. Thus, novel inhibitors that target both mTORC1 and mTORC2; or mTORC1, mTORC2, and PI3K; or combination treatments involving mTORC1-targeting agents and MAPK inhibitors might have the potential to overcome resistance to mTORC1 inhibitors. Finally, as it has been reported that rapalogs or ATP-competitive mTOR inhibitors increase RTK expression that results in PI3K-dependent AKT activation or Ras-dependent MAPK activation [33], combining PI3K/AKT/mTOR inhibitors with tyrosine kinase inhibiters (TKI) might have therapeutic advantages over the use of PI3K/AKT/mTOR inhibitors alone. Future directions Combining PI3K/AKT/mTOR inhibition with other targeted agents The early results from clinical trials involving advanced solid tumors are rather sobering [3,27]. The relatively modest single-agent activity of PI3K/AKT/mTOR inhibitors, especially when compared with that of agents targeting driver oncogenes such as BCR-ABL, BRAF, or anaplastic lymphoma kinase (ALK), indicates that oncogene addiction to PI3K/ AKT/mTOR signaling is not absolute in ovarian cancer. Thus, it is necessary to combine PI3K/AKT/mTOR inhibitors with other targeted agents in order to unleash their full potential as treatments for ovarian cancer. Greater clinical responses might be achieved by combining PI3K/ AKT/mTOR inhibitors with other targeted agents. Considering the potential resistance mechanisms mentioned above, combining PI3K/AKT/ mTOR inhibitors with TKI is worth investigating. As preclinical and clinical investigations have suggested that cancer cells that exhibit activating mutations in the KRAS gene are relatively resistant to PI3K/AKT/ mTOR inhibition [34], the combination of PI3K/AKT/mTOR inhibitors with drugs that target Ras/Raf/mitogen activated kinase kinase (MEK)/ extracellular-signal-regulated kinase signaling is another attractive strategy. In a preclinical investigation involving a KRAS-driven lung cancer model, an MEK inhibitor and the dual PI3K–mTOR inhibitor NPVBEZ235 demonstrated synergistic effects [35]. Another interesting combination is the use of PI3K inhibitors together with poly-ADP ribose polymerase (PARP) inhibitors. Preclinical investigations have demonstrated that PI3K inhibition is associated with the loss of homologous recombination repair capacity, increased DNA damage, and more sensitization of breast cancer cells to PARP inhibitors [36]. It has recently been suggested that PTEN is also involved in the maintenance of genomic stability and that the loss of PTEN function results in defective homologous recombination-mediated repair of DNA double-strand breaks. A phase I trial of combined treatment involving the PARP inhibitor olaparib and pan-PI3K inhibitors is currently enrolling patients with triple-negative breast cancer and high-grade serous ovarian cancer (Table 1). We consider that this combination is worth investigating in patients with OCCC, in which loss of PTEN expression is observed in 40% of cases [20].
Patient selection To develop clinically effective treatments, it is crucial to identify subgroups of patients that are most likely to benefit from PI3K/AKT/mTOR inhibition-based therapy using reliable biomarkers. Previous preclinical investigations have suggested that ovarian cancer cells exhibiting PIK3CA mutations, PTEN loss, the hyperactivation of AKT/mTORC1 signaling, or cyclin D1 overexpression are particularly sensitive to AKT/ mTORC1 inhibitors [37]. However, a recent preclinical investigation using 17 well-characterized ovarian cancer cell lines suggested that AKT activation was necessary but not sufficient to induce sensitivity to AKT inhibitors in ovarian cancer [34]. Despite the phosphorylation and activation of AKT, cancer cell lines with activating mutations in the KRAS gene or inactivating mutations in the retinoblastoma (RB) gene were found to be relatively resistant to AKT inhibition [34]. Consistent with this finding, a recent clinical report suggested that PI3K/AKT/ mTOR inhibition might be most effective against ovarian tumors that possess activating mutations in the PIK3CA gene, whilst activating mutations in the KRAS gene are likely to be a predictor of resistance [38]. The potential of these candidate biomarkers to predict the sensitivity of ovarian tumors to PI3K/AKT/mTOR inhibitors needs to be investigated in the prospective setting in future clinical trials. Potential as chemopreventive agents Recently, it has been demonstrated that PTEN and ARID1A double knockout mice developed ovarian endometrioid or undifferentiated carcinoma, whereas ARID1A knockout mice did not develop histological alterations [39], indicating that PI3K/AKT/mTOR inhibitors have potential as chemopreventive agents. As consistent with this, using TgMISIIR-TAg transgenic mice that develop ovarian cancer accompanied by ascites and peritoneal dissemination, our group demonstrated that mTORC1 inhibition by everolimus treatment markedly delayed tumor development and progression [40]. Thus, the potential of PI3K/AKT/ mTOR inhibitors to prevent or delay the onset of ovarian cancer might be worth investigating, especially in women who are at high risk of the disease. Conclusions The PI3K/AKT/mTOR signaling pathway is frequently activated in ovarian cancer. On the basis of promising preclinical findings, inhibitors targeting this pathway are currently being evaluated as treatment strategies for ovarian cancer, either monotherapy or in combination with cytotoxic agents. A greater focus on patient selection based on predictive biomarkers, a deeper understanding of the mechanisms responsible for resistance, and the identification of effective treatment combinations will maximize the potential of PI3K/AKT/mTOR inhibitors. Solving these problems will aid the development of optimal PI3K/AKT/mTORtargeting therapies for ovarian cancer. Conflicts of interest statement The authors declare that they have no conflicts of interest.
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Please cite this article as: Mabuchi S, et al, The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer, Gynecol Oncol (2015), http:// dx.doi.org/10.1016/j.ygyno.2015.02.003
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