Activation of PI3K/Akt/mTOR Pathway and Dual ...

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and mTOR inhibitor temsirolimus were effective to EC cell lines with PIK3CA or PTEN mutations [107]. Fig. (2). Inhibitors of PI3K/Akt/mTOR pathway used in.
Send Orders for Reprints to [email protected] Current Medicinal Chemistry, 2014, 21, 3070-3080

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Activation of PI3K/Akt/mTOR Pathway and Dual Inhibitors of PI3K and mTOR in Endometrial Cancer Jiezhong Chen1,*, Kong-Nan Zhao2, Rui Li1, Renfu Shao3 and Chen Chen1,* 1

School of Biomedical Sciences, University of Queensland, St Lucia QLD4072, Australia; 2Centre for Kidney Disease Research-Venomics Research, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, QLD 4102, Australia; 3GeneCology Research Centre, Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Maroochydore, QLD 4556, Australia Abstract: Endometrial cancer is the third most common cancer in women. Endometrial carcinomas (EC) are clinic histologically classified into two types. Type I tumours, which account for 80% of ECs, are estrogen-dependent and are low grade. Type II tumours are more aggressive with invasion into myometrium. Recently a new classification for endometrial cancer has been proposed based on molecular markers. Whether this classification is helpful for clinical management of endometrial cancer remains to be tested. At present, treatment outcomes of endometrial cancer are not satisfactory. Therefore, more effective approaches are sought. This review summarizes the recent studies about activation of PI3K/Akt pathway in EC and therapeutic implications of the inhibitors of the pathways with emphasis on dual inhibitors of PI3K and mTOR. Both genetic defects and environmental factors are involved in carcinogenesis and progression of EC via activation of multiple signal pathways including the PI3K/Akt pathway. Mutations of major components of the PI3K/Akt pathway are common in EC. Type I tumours usually have mutations in Ras, PTEN, PIK3CA, AKT1, beta-catenin and type II tumours have mutations in TP53. Environmental factor like obesity can also activate the PI3K/Akt pathway to increase the incidence of EC and to cause poorer prognosis. Therefore, inhibition of the PI3K/Akt pathway can be used for therapy of the disease. At present, mTOR inhibitors have been extensively studied and tested in clinical trials. A newly synthesised dual inhibitor of PI3K and mTOR BEZ235 has been shown to be more effective than mTOR inhibitor rapamycin. BEZ235 can inhibit feedback activation of PI3K/Akt pathway by rapamycin. It is promising to include effective PI3K/Akt inhibitors in current treatment regime of endometrial cancer to improve the therapeutic efficacy.

Keywords: Endometrial cancer, PI3K/Akt, PIK3CA, PTEN, Ras. INTRODUCTION Endometrial cancer is the third most common cancer in women [1]. ECs are classified into two types according to histopathology, molecular profiling, and clinical behaviour [2]. Type I ECs are endometrioid that express both estrogen receptor (ER) and progesterone receptor (PR) and thus are sensitive to hormone therapy [2]. Type I ECs are usually less aggressive and rarely metastasize and thus have a good prognosis with a 5-year survival rate of 80–85% [3]. Type II ECs are those of non-endometrioid histology but serous or more clear-cell morphology [4]. Type II ECs are not sensitive to estrogen and progesterone, and thus difficult to treat. They are poorly differentiated and highly aggressive with myometrial invasion. Therefore, type II ECs have a poor prognosis with 5 year survival rate less than 35% [5-8]. Recently a new classification for endometrial cancer has been proposed based on molecular markers [9]. Whether new classification is helpful for clinical management of *Address correspondence to these authors at the School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia; Tel: 61-7-33653856; Fax: 61-7-33652398; E-mail: [email protected] and [email protected] 1875-533X/14 $58.00+.00

endometrial cancer still needs to be tested. Epidemiological studies have shown that ECs are the most common gynaecologic malignancy with estimated 52,630 new cases and 8590 deaths in year 2014 in the United States, particularly the cases of endometrial cancer are increasing each year [10]. At present, there are no effective treatment approaches for metastasized endometrial cancer [11]. Therefore, a novel effective approach is urgently needed. At present, the first choice for the treatment of the disease is surgery [12]. It is effective to cure early-stage endometrial cancer. However, those unable to be removed by surgical procedures will be treated with chemotherapy, radiotherapy and hormone therapy [13, 14]. These therapies can also be used as adjuvant measures after surgery to reduce recurrence and improve survival. However, the responses are weak and survival rate is not significantly improved. Therefore, more effective approaches are sought such as targeted therapy against activated signal pathways in endometrial cancer. Multiple signalling pathways are important for carcinogenesis and have been shown to be involved in endometrial cancer such as PI3K and Wnt, VEGF and EGFR [1517]. Inhibition of EGFR, VEGFR and PI3K/PTEN/Akt/ mTOR has been in clinical trials but the responses are modest [18-21]. © 2014 Bentham Science Publishers

Activation of PI3K/Akt/mTOR Pathway and Dual Inhibitors

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The endometrial cancer is affected by both environmental factors and genetic mutations [22]. For example, obesity has been considered to be the most important risk factor for endometrial cancer [23-25]. Multiple cancer risk factors elevated in obesity may activate several survival signal pathways to increase endometrial cancer incidence including PI3K/Akt, MAPK and Stat3. Many gene mutations have also been identified in endometrial cancer. Interestingly most mutations in endometrial cancer happen in the major components of the PI3K/Akt pathway such as K-ras, PTEN, PIK3CA, Akt1, TP53 and beta-catenin [26, 27]. The phenotypes are correlated with genetic changes with type I tumors having K-ras, PTEN, PIK3CA, Akt and beta-catenin mutations [28]. Mutations in TP53 have been found to be common in type II tumours, accounting for about 90% of type II cases [29]. Fig. (1) shows the gene mutations that often occur in endometrial cancer. Activation of the PI3K/Akt pathway in endometrial cancer has been associated with increased cancer initiation by increasing chromosomal instability [30]. It has been demonstrated that activation of the PI3K/Akt pathway either by PTEN-loss mutation or Akt-activating mutation is sufficient to cause the cancer [31]. Activation of the PI3K/Akt signal pathway is also well known to cause drug resistance to chemotherapy [32, 33]. Therefore, targeted therapy against this pathway is promising to improve treatment outcome for endometrial cancer [34]. In this review, we summarise the activation of the PI3K/Akt pathway and the application of inhibitors of the major components of the pathway in endometrial cancer.

ACTIVATION OF PI3K/Akt PATHWAY IN ENDOMETRIAL CANCER CAUSED BY GENE MUTATIONS The PI3K/Akt pathway is a major survival pathway [35]. It is frequently activated in many cancers such as breast, bladder, colon, prostate, thyroid, ovarian and NSCLC and is associated with drug resistance [32, 36, 37]. Targeted therapy with small molecules is developed for the treatment of these cancers [38-42]. The activation of the PI3K/Akt pathway in endometrial cancer could be caused by mutations of genes encoding its components such as Ras, PTEN, PIK3CA, PIK3R1 and PIK3R2. It can also be activated by other factors such as obesity. Ras-Gene K-ras is an oncogene that can activate both PI3K and ERK pathways. Ras can interact with catalytic subunit of PI3K – p110 and activate PI3K activity independent of PI3K regulatory subunit p85 [43]. It has been shown that K-ras activating mutations occur in 10-20% cases of endometrial cancer and the mutations have been found at codon 12 of K-ras [44]. One mutation (Gly-Ala) was found in grade I or early clinic-stage cancer and another mutation (Gly-Cys) was found in grade III or more developed late clinic-stage cancer. It has been shown that K-ras mutations lead to adverse outcome in postmenapause women [45]. Kato et al. compared two cell lines with Kras wild type (Ishikawa) and K-ras (HHUA) mutated and found that EGF stimulated Ishikawa but not HHUA [46]. Inhibition of EGFR decreased Ishikawa growth but not HHUA. K-ras has been shown to have synergistic effect with PTEN in

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Fig. (1). Common gene mutations in endometrial cancer. PI3K/Akt pathway is often activated in endometrial cancer by mutations of its components. Genes for PI3K, Akt and beta-catenin could be activated while genes for PTEN and p53 could be inactivated. Activation of the PI3K/Akt pathway leads to increased cell growth via mTOR, increased transcription via beta-catenin and decreased apoptosis via p53. (+) represents activating mutations, () represents inactivating mutations.

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tumorogenesis in mice [47]. K-ras has been associated with microsatelite instability and this is probably via methylation status [48, 49]. K-ras has been shown to increase raf and estrogen receptor for tumoriogenesis [50]. PTEN Gene Lipid phosphatase PTEN is a tumor suppressor, which catalyses PIP3 to PIP2, an effect opposite to PI3K [51, 52]. PTEN inactivating mutations are the most often mutations in endometrial cancer. PTEN inactivating mutations produce non-functional PTEN proteins, leading to increased PIP3 or activation of the PI3K pathway [51, 52]. However, PTEN mutations only account for part of the loss of PTEN protein. A study showed that PTEN protein loss is detected in 64% of the cases of endometrial cancer but sequence abnormalities only account for 43% of the cases [53]. In wild type of PTEN sequences, 44% patients have decreased PTEN proteins [53]. Loss of PTEN protein can increase phosphorylation of Akt, which in turn causes a cascade of alteration of its target proteins to increase cell proliferation and decrease apoptosis. PTEN deficiency has been associated with genomic stability which is a major defect responsible for carcinogenesis [54]. The causal relationship between PTEN mutation and endometrial cancer has been established in animal models [55]. In a mouse model, PTEN knockout developed endometrial cancer independent of estrogen [56]. There are synergistic effect of PTEN mutation and other mutations in carcinogenesis. Kim et al. (2010) showed that Mig-6 and PTEN deficiency had also synergistic effect [57]. K-ras activating mutation and PTEN inactivating mutation also produced higher potent to cause cancer [47]. Endometrial cancer patients with both PTEN and TP53 mutations exhibited poorer prognosis than those with a single mutation of PTEN or TP53 as evidenced by an epidemiological study [58]. PIK3CA Gene The main enzyme in the PI3K/Akt pathway is PI3K. It can convert PIP2 into PIP3, which in turn activates Akt [59]. There are three classes of PI3K of which class IA is most related to cancer. Each PI3K enzyme is composed of a regulatory subunit p85 and a catalytic subunit p110. P110 has three isoforms: alpha, beta and sigma. PIK3CA gene encodes the PI3K catalytic subunit p110 alpha and activating mutations of PIK3CA has been found frequently in many cancers. Activating mutations of PIK3CA produce highly active form of PI3K, resulting in increased downsteam protein activities [59]. The activating mutations of PIK3CA have been associated with overgrowth of epithelial cells and cancer [60]. Activating mutations in PIK3CA in endometrial cancer have been investigated by several studies [61]. Konopka et al. (2011) investigated 196 endometrial carcinomas and found 20% had mutations and 12.2% had amplification [62]. Velosco et al. (2006) detected 24% of PIK3CA mutations in emdometrial cancer samples [63]. Oda et al. (2006) tested gene mutations of PTEN and PIK3CA in 66 endometrial cancer patients and found that 36% patients had PIK3CA mutations and 26% had both PTEN and PIK3CA mutations [64]. Hayes et al. (2005) also found that mutation of PIK3CA was

Chen et al.

more frequent in endometrial cancer samples with PTEN mutations than that without PTEN mutations [27]. The mutations mostly happen in exon 9 and exon 20. PIK3CA activating mutation has been shown to increase the invasive ability of cells [65]. In breast cancer and colon cancer PIK3CA mutation decreased survival rate [66, 67]. But in endometrial cancer, it was found that PIK3CA mutation alone did not affect survival rate, but decreased survival rate in patients with TP53 mutation. The activating mutation of PIK3CA and the deficiency of PTEN have synergistic effect [63]. Knockdown of PTEN in Ras or PIK3CA mutated cells further increased pAkt [64], indicating the synergistic effect of two mutations from their roles in the activation described above. PIK3R1 and 3R2 Genes PIK3R1 and PIK3R2 encode the regulatory subunits of PI3K – p85alpha and p85 beta respectively. The protein p85 binds to p110 catalytic subunit to inhibit its activity. Recently, Cheung et al. found the mutations of PIK3R1 and PIK3R2 in endometrial cancer patients [68, 69]. These mutations decrease the inhibitory ability of p85 on p110, leading to increased activity of the PI3K/Akt pathway [68, 69]. Another group has also studied the mutation of PIK3R1 in 42 EEC and 66 NEEC [70]. High frequency of PIK3R1 mutations were found with 43% in EEC and 12% in NEEC. The mutated p85 was demonstrated to be unable to bind to p110 and thus, unable to inhibit p110, which could lead to increased level of pAkt. Akt1 Gene Akt is a major component of the PI3K/Akt pathway. It regulates a broad range of downstream target proteins to control cell proliferation and apoptosis. Cohen et al. (2010) found that 4% endometrial cancer patients had Akt1 activating mutation [71]. The mutation point was identified in Pleckstrin homology domain of Akt 1, which can lead to increased Akt activity [70]. The mutation rate, however, is very low. Only 2 out of 89 human EC samples were Akt1 mutated while no mutations were found in 12 cell lines examined. Nevertheless, the finding indicates that activating mutations of Akt1 can also contribute to the activation of the PI3K/Akt/mTOR pathway in endometrial cancer. Beta-Catenin Beta-catenin is a nuclear transcriptional factor, regulating several genes important in carcinogenesis [72]. pAkt can phosphorylate GSK-3beta and release beta-catenin from the complex and then after translocating into nucleus, beta-catenin can increase the expression of its downstream target genes [35]. Beta-catenin is also regulated by Wnt signal pathway. In EC, it has been detected that beta-catenin is mutated in some cases, leading to accumulation of beta-catenin, which promotes gene transcription of oncogenes [73]. Beta-catenin mutation has been detected in 23% of endometrial cancer [74]. TP53 Gene TP53 gene encodes p53, which is a tumor suppressor. P53 is activated by environmental stimulators and initiate

Activation of PI3K/Akt/mTOR Pathway and Dual Inhibitors

cell apoptosis to reduce carcinogenesis [75]. The inactivating mutations of TP53 have been found in endometrial cancer and have been associated with poor prognosis of the disease [76, 77]. Inactivation of TP53 results in decreased cell apoptosis and thus increased carcinogenesis [75]. Knockout of TP53 gene in mice resulted in a type II endometrial cancer and introduction of p53 suppressed the development of EC in the mouse model [77]. mTOR mTOR is an atypical protein kinase and responses to growth factors, nutrients and energy levels [78, 79]. It is downstream of Akt and targets 6SK and 4EBP1 to mediate cell proliferation, cell growth and metabolism [80, 81]. It has been extensively studied in many cancers and is used as a therapeutic target [82]. Over-expressed mTOR has been found in endometrial cancer [83]. A study has also shown that in endometrial cancer, p-mTOR levels are collated with p-4EBP1 and PTEN deficient in 57 patients [84]. Their expression is related with poor prognosis and more sensitive to rapamycin. ACTIVATION OF PI3K/AKT PATHWAY IN ENDOMETRIAL CANCER CAUSED BY ENVIRONMENTAL FACTORS Many factors in the microenvironment of endometrial cancer may also activate PI3K/Akt pathway, leading to increased carcinogenesis and drug resistance to anti-cancer therapy. Epidemiological studies have demonstrated that obesity is most associated with endometrial cancer [85]. In obesity, many cancer risk factors are altered including insulin/IGF-1 axis, adipokines, interleukins, TNF-alpha and estrogen [35, 36, 86]. All these factors can activate PI3K/Akt pathway [36, 37]. Their effects on the pathways are discussed below. Insulin and IGF-1 are well known to regulate cell proliferation and apoptosis due to their ability to activate the PI3K/Akt pathway via insulin receptor (IR) and IGF-1 receptor (IGF-1R) [36, 87, 88]. Insulin-activated PI3K/Akt pathway has been demonstrated to cause drug resistance in colon cancer and melanoma [36, 37, 89]. Inhibition of the pathway by Ly294002 and BEZ-235 reduced such drug resistance. Epidemiological studies have demonstrated that high levels circulating insulin increase endometrial cancer incidence [90, 91]. Several studies have shown that insulin can activate the PI3K/Akt pathway in EC [92-95]. In vitro, over-expression of IR promoted endometrial cancer cell growth [96]. Direct addition of insulin to cultured endometrial cancer cell line Ishikawa increased cell proliferation and decreased apoptosis via InsR/PI3K/Akt pathway [93]. It has also been shown that NVP-AEW541, an inhibitor of IGF-1R abolished IGF-1 stimulated PI3K/Akt pathway and cell proliferation, indicating its therapeutic implication [97]. Leptin is a major adipokine produced by adipocyte [98]. In obesity, leptin production is increased due to increased adipocyte size and number [99-102]. The signalling pathways is only mediated by lepting receptor b although there are totally 6 leptin receptors identified [103]. Leptin can activate several signalling pathways to cause cancer cell proliferation and drug resistance [103, 104]. Silencing of leptin

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receptor b decreased drug resistance and its downstream pathways PI3K and MAPK [103]. Inhibition of PI3K/Akt pathway by BEZ235 also reduced drug resistance, suggesting multiple approaches could be used for overcoming environmental factor-induced drug resistance. Leptin has also been demonstrated to increase PI3K/Akt activity in endometrial cancer cell lines [105] Increased estrogen in obesity-associated endometrial cancer leads to poor prognosis via activation of PI3K/Akt pathway and its down-stream target. Zhang et al. (2012) showed that addition of estrogen into cultured endometrial cancer cell lines increased activity of the PI3K/Akt and MAPK pathways, leading activation of fat mass and obesityassociated (FTO) gene that is associated with increased endometrial cancer cell proliferation and invasion [106]. Overall, many environmental factors can activate PI3K/Akt pathways via their receptors. Activation of the pathway can cause increased carcinogenesis and drug resistance in the treatment. Multiple approaches may be taken to inhibit the environmental factor-induced PI3K/Akt pathway. INHIBITION OF THE PI3K/Akt PATHWAY IN THE TREATMENT OF ENDOMETRIAL CANCER Endometrial cancer can be removed by surgical procedure if it is diagnosed at the early stage. However, those unremovable have to be treated with chemotherapeutic agents. The outcomes of the treatment for the disease are not satisfactory. Therefore, more effective approaches are needed. As PI3K/Akt pathway is activated in EC, inhibition of the pathway has been applied for the treatment of the disease (Fig. 2). mTOR inhibitors have been extensively studied. Recently dual inhibitors of PI3K and mTOR have also been investigated in EC cancer cell lines and animal models. A recent study showed that dual PI3K/mTOR inhibitor GDC-0941 and mTOR inhibitor temsirolimus were effective to EC cell lines with PIK3CA or PTEN mutations [107].  &.

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Fig. (2). Inhibitors of PI3K/Akt/mTOR pathway used in endometrial cancer. Temsirolimus, Everolimus, Ridaforolimus inhibit mTOR only; Bez235, GDC-0491, PF-04691502 and PF05212384 inhibit both PI3K and mTOR.

mTOR Inhibitor Several rapamycin analoques have been tested for the treatment of EC. The effect has been moderate. Rapamycin is a traditional inhibitor of mTOR; second generation has now been developed [108]. Recent findings showed that Torin 1 is an efficient inhibitor of mTOR which can inter-

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feres with some downstream targets that are not inhibited by rapamycin [78]. It will be worth of testing the effect of torin 1 in endometrial cancer. Temsirolimus Temsirolimus is an ester derivative of rapamycin, which has been in clinical trials for several cancers including endometrial cancer [109, 110]. The addition of OH group has resulted in anti-angiogeneis effect of temsirolimus [111] (Table 1). It has been shown to inhibit both VEGF (vascular endothelial growth factor) and VEGF-driven endothelial cell proliferation in vitro and vessels formation in vivo [111]. Temsirolimus has been used for clinical trials [112-118]. A phase II study evaluated the effect of temsirolimus on recurrent or metastatic endometrial cancer. The dosage used is 25mg weekly by intravenous administration with 4 weeks as a cycle [119]. Results showed that temsirolimus modestly improved EC with better responses in chemotherapy-naive patients than that in chemotherapy-treated group (14 % vs 4% partial response and 69% vs 48% stable disease). This relationship has been confirmed by another recent phase II clinical trial [113]. The most common side-effect reported is lung toxicity when single temsirolimus was used [120]. Combination of temsirolimus and topotecan resulted in myosuppression [121]. These side-effects are tolerated by patients who did not have pelvic radiotherapy but not by those with RT history. Combination therapy of temsirolimus with bevacizumab has been shown to increase treatment efficacy in a phase II trial. The side-effects, however, were also increased [122]. Everolimus (RAD-001) Everolimus (RAD-001) is a derivative of sirolimus by introduction of 40-O-(2-hydroxyethyl) and works similarly to sirolimus as an inhibitor of mTORC1 [123, 124]. Everolimus binds to its protein receptor FKBP12, which directly interacts with mTORC1 and inhibit its activity. Preclinical studies in animal models showed that everolimus was effective against endometrial cancer [123, 124]. Therefore, it is currently used for clinical trials [125-129]. A Phase I study of everolimus showed prolonged survival time for endometrial cancer patients [130]. Several Phase II studies have shown that everolimus is effective in chemotherapy resistant EC [126, 131]. Combination therapy can also increase the efficacy of everolimus, for example, it has synergistic effects with genifinib [132] and tamoxifen [133]. Ridaforolimus Ridaforolimus (AP-23573) is a nonprodrug analogue of rapamycin and strongly inhibits mTOR and has been used in clinical trials for solid cancers [134-138]. It has also been evaluated for endometrial cancer both in cell lines and animal models [139-141]. The study showed that ridaforolimus inhibited the proliferation of all 6 endometrial cancer cell lines tested including HEC-1-A, HEC-1-B, KLE, AN3-CA, RL95-2 and SK-UT-1B. The inhibition was achieved at nanomolar levels and was more sensitive in PTEN deficient cell lines. Ridaforolimus reduced tumour growth in a xenograft endometrial model in mice [139]. The downstream targets of mTOR, 4E-BP1 and ribosomal protein S6 phos-

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phorylations were decreased. A phase-II study showed that Ridaforolimus as a single agent had anti-cancer activity to endometrial cancers and was well tolerated by patients [137]. Combination of ridaforolimus with fibroblast growth factor receptor (FGFR) inhibitor ponatinab produced synergistic effects on endometrial cancer cells with mutated FGFR in both in vitro and in vivo [140]. The combination regime could be worth clinical trials. Dual Inhibitor Dual inhibition of PI3K and mTOR has advantage to overcome the rebounce of PI3K due to the feedback loop caused by mTOR inhibition [142]. It has been shown that combinational use of PI3K and mTOR inhibitors increases therapeutic effectiveness. Oda et al. (2011) has tested a dual inhibitor called inhibitor P in endometrial cancer cell lines and showed PTEN mutated cell lines are more sensitive to inhibitor P [143]. Recently, more compounds that can inhibit both PI3K an mTOR have been synthesised and tested preclinically. For example, GDC-0941 has been tested to be effective in EC cell lines with increased PI3K/Akt activity due to PIK3CA and PTEN mutations [107, 144]. It is under clinical trials but no reports have been published yet. PF04691502 and PF-05212384(PKI-587) have been demonstrated efficacy in animal models and entered to clinical clinical trials although PF-04691502 was tested in cancers other than endometrial cancer [145-148]. BEZ235 has been studied most extensively [149, 150]. A recent study has investigated the effect of BEZ235 in comparison with rapamycin in endometrial cancer. In 13 endometrial cancer cell lines, the 9 cell lines that have PTEN mutations or both PTEN and PIK3CA mutations are more sensitive to BEZ235 ( IC50 less than 100nM) while the other 4 cell lines with Kras or K-ras plus PIK3CA mutations are less sensitive (IC50 more than 100nM) [151]. Western blotting showed that BEZ235 inhibited pAkt, GSK3beta and mTOR down stream target proteins S6 and 4EBP1. The inhibition of PI3K/Akt pathway has been shown to result in G1 arrest. Furthermore, BEZ235 significantly inhibited tumor growth in an animal model with xenografted endometrial cancer cell lines. CONCLUSION The PI3K/Akt pathway is activated in most endometrial cancer. Different components of the pathway have been detected to have mutations such as K-ras, PTEN, PIK3CA, Akt1, TP53 and beta-cantenin. Therefore, inhibition of the pathway can be used for the treatment of endometrial cancer. Several mTOR inhibitors have been shown to have modest effect. The discovery of dual inhibitors that can inhibit both PI3K and mTOR promises a novel effective approach for targeted therapy against PI3K/Akt pathway in endometrial. BEZ235 inhibited cell growth and reduced xenograft tumor size and is more effective than rapamycin. Several dual inhibitors have also been shown to have better effectiveness and have been used for clinical trials. But these inhibitors may not be effective to those cell lines that either have mutations down from Akt and mTOR such as TP53 and betacatenin genes or mutations in MAPK pathway such as K-ras (Fig. 2).

Activation of PI3K/Akt/mTOR Pathway and Dual Inhibitors

Table 1.

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Structure and mechanisms of some common inhibitors of the PI3K/Akt pathway. Structure From: http://www.chemblink.com/index.htm

Name

Mechanism/SAR

Preclinical Refs

Clinical Refs

An ATP-Competitive Inhibitor of mTOR with increased anti-agiogenesis due to addition of 42-OH at Rapamycin

[111]

[112-118]

A derivative of sirolimus by 40-O-(2hydroxyethyl) Everolimus binds to its protein receptor FKBP12, leading to inhibition of mTORC1 activity

[123, 124]

[125-129]

An anologue of rapamycin Increased affinity binding to FKBP and their more effective due to structure change: C-43 secondary alcohol moiety of the cyclohexyl group of rapamycin with substituted phosphonate and phosphinate groups

[140, 141]

[135-138]

An ATP-competitive inhibitor, binding the ATP-binding pocket of PI3K and mTOR

[144]

No reports

An ATP-competitive inhibitor, binding the ATP-binding pocket of PI3K and mTOR

[149, 150]

No reports

HO HO O O O

Temsirolimus

O

O

OH

N O HO

O

O

O O

O

O O

N

H

O

O

O

OH

O

H

OH

Everolimus (RAD-001)

OH H

O

O

O

O O

N O

Ridaforolimus

O OH

H

O

O

P

O

H

O OH O

O

O

O

O N S

GDC-0941 (Pictilisib)

N

N

N

NH

N

N O S O

O

BEZ235 (NVP-BEZ235)

N N

N N

N

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Chen et al. (Table 1) contd…. Mechanism/SAR

Preclinical Refs

Clinical Refs

An ATP-competitive inhibitor, binding the ATP-binding pocket of PI3K and mTOR

[146]

[145] not in EC

An ATP-competitive inhibitor, binding the ATP-binding pocket of PI3K and mTOR

[147]

[148]

Structure From: http://www.chemblink.com/index.htm

Name

OH

PF-04691502

NH2

O

N

N

O

N

N O

O N

PF-05212384 (PKI-587)

N N

N

O

N

O

O N H

N N H

N

CONFLICT OF INTEREST

[3]

The authors confirm that this article content has no conflict of interest.

[4]

ACKNOWLEDGEMENT

[5]

Declared none. ABBREVIATIONS EC

=

Endometrial cancer

EEC

=

Endometrioid endometrial cancer

ERK

=

Extracellular signal-regulated kinases

NEEC

=

Non-endometrioid endometrial cancer

PI3K

=

Phosphoinositide 3-kinase

[6]

[7]

PIK3CA =

A gene encoding phosphatidylinositol-4,5bisphosphate 3-kinase, catalytic subunit alpha

Akt

=

Protein kinase B

mTOR

=

Mammalian target of rapamycin

[10]

Wnt

=

Wingless-int

[11]

VEGF

=

Vascular endothelial growth factor

EGFR

=

Epidermal growth factor receptor

K-ras

=

Kirsten rat sarcoma viral oncogene homolog

PTEN

=

Phosphatase and tensin homolog

[8] [9]

[12]

[13] [14]

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[2]

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Received: November 28, 2013

Revised: March 13, 2014

Accepted: April 02, 2014

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