The Potential of PI3K/AKT/mTOR Signaling as a Druggable Target for Endometrial and Ovarian Carcinomas

Author(s): Csongor György Lengyel*, Sara Cecilia Altuna, Baker Shalal Habeeb, Dario Trapani, Shah Zeb Khan

Journal Name: Current Drug Targets

Volume 21 , Issue 10 , 2020


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Graphical Abstract:


Abstract:

Aims: In this narrative review, we summarize the role and significance of PI3K-AKTmTOR (PAM) pathway in ovarian and endometrial cancers, providing the most recent and relevant literature on the topic and addressing options for targeting PAM along with future perspectives of drug development.

Background: Alterations of the PAM-pathway are common in both endometrial and ovarian cancers, and are described in specific histology-defined subtypes. PAM seems to be involved in critical steps of endometrial and ovarian carcinogenesis, often mechanistically involved in the acquisition of a phenotype of treatment resistance, which could be targetable. However, early clinical trials with PAMinhibitors (PAMi) have provided disappointing results, particularly when non isoform-specific inhibitors were tested in unselected populations, accompanied by an adverse safety profile. Since then, more encouraging observations have been collected when targeting specific isoforms of PAM proteins with more selective drugs, resulting in encouraging activity and more manageable toxicity.

Conclusion: Although the rationale of inhibiting the PAM-pathway has been demonstrated in several promising preclinical studies, no Phase III clinical trial is available to demonstrate a significant benefit of PAM-inhibitors. A way to manage targeted agents is to tailor their use to particular subpopulations most likely to obtain a considerable benefit, namely pursuing an individualized, precision-medicine approach.

Keywords: PI3K-AKT-mTOR pathway, precision medicine, targeted therapy, ovarian cancer, endometrial cancer, gynaecological cancer, platinum resistance.

[1]
International agency for research on cancer. global cancer observatory 2019, September 5.Available from:. http://gco.iarc.fr/
[2]
Pistritto G, Trisciuoglio D, Ceci C, Garufi A, D’Orazi G. Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies. Aging (Albany NY) 2016; 8(4): 603-19.
[http://dx.doi.org/10.18632/aging.100934] [PMID: 27019364]
[3]
Cheng JC, Auersperg N, Leung PCK. Inhibition of p53 induces invasion of serous borderline ovarian tumor cells by accentuating PI3K/Akt-mediated suppression of E-cadherin. Oncogene 2011; 30(9): 1020-31.
[http://dx.doi.org/10.1038/onc.2010.486] [PMID: 20972462]
[4]
Decker B, Pumiglia K. mTORc1 activity is necessary and sufficient for phosphorylation of eNOS(S1177). Physiol Rep 2018; 6(12): e13733-.
[5]
Malloy KM, Wang J, Clark LH, et al. Novasoy and genistein inhibit endometrial cancer cell proliferation through disruption of the AKT/mTOR and MAPK signaling pathways. Am J Transl Res 2018; 10(3): 784-95.
[PMID: 29636868]
[6]
Ahn J-H, Lee K-T, Choi YS, Choi J-H. Iloprost, a prostacyclin analog, inhibits the invasion of ovarian cancer cells by downregulating matrix metallopeptidase-2 (MMP-2) through the IP-dependent pathway. Prostaglandins Other Lipid Mediat 2018; 134: 47-56.
[http://dx.doi.org/10.1016/j.prostaglandins.2017.12.002] [PMID: 29292033]
[7]
Dobbin ZC,, Landen CN. The importance of the PI3K/AKT/MTOR pathway in the progression of ovarian cancer. Int J Mol Sci 2013; 14(4): 8213-27.
[http://dx.doi.org/10.3390/ijms14048213] [PMID: 23591839]
[8]
Carnero A, Blanco-Aparicio C, Renner O, Link W, Leal JF. The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Curr Cancer Drug Targets 2008; 8(3): 187-98.
[http://dx.doi.org/10.2174/156800908784293659] [PMID: 18473732]
[9]
Carnero A. The PKB/AKT pathway in cancer. Curr Pharm Des 2010; 16(1): 34-44.
[http://dx.doi.org/10.2174/138161210789941865] [PMID: 20214616]
[10]
Polivka J Jr, Janku F. Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol Ther 2014; 142(2): 164-75.
[http://dx.doi.org/10.1016/j.pharmthera.2013.12.004] [PMID: 24333502]
[11]
Noorolyai S, Shajari N, Baghbani E, Sadreddini S, Baradaran B. The relation between PI3K/AKT signalling pathway and cancer. Gene 2019; 698: 120-8.
[http://dx.doi.org/10.1016/j.gene.2019.02.076] [PMID: 30849534]
[12]
Fain JN. Regulation of phosphoinositide-specific phospholipase C. Biochimica et Biophysica Acta (BBA) -. Molecular Cell Research 1990; 1053(1): 81-8.
[13]
Zhao W, Qiu Y, Kong D. Class I phosphatidylinositol 3-kinase inhibitors for cancer therapy. Acta Pharm Sin B 2017; 7(1): 27-37.
[http://dx.doi.org/10.1016/j.apsb.2016.07.006] [PMID: 28119806]
[14]
Mazloumi Gavgani F, Smith Arnesen V, Jacobsen RG, et al. Class I Phosphoinositide 3-Kinase PIK3CA/p110α and PIK3CB/p110β Isoforms in Endometrial Cancer. Int J Mol Sci 2018; 19(12) E3931
[http://dx.doi.org/10.3390/ijms19123931] [PMID: 30544563]
[15]
Khabele D, Kabir SM, Dong Y, Lee E, Rice VM, Son D-S. Preferential effect of akt2-dependent signaling on the cellular viability of ovarian cancer cells in response to EGF. J Cancer 2014; 5(8): 670-8.
[http://dx.doi.org/10.7150/jca.9688] [PMID: 25258648]
[16]
Ruan G-X, Kazlauskas A. Axl is essential for VEGF-A-dependent activation of PI3K/Akt. EMBO J 2012; 31(7): 1692-703.
[http://dx.doi.org/10.1038/emboj.2012.21] [PMID: 22327215]
[17]
Irusta G, Abramovich D, Parborell F, Tesone M. Direct survival role of vascular endothelial growth factor (VEGF) on rat ovarian follicular cells. Mol Cell Endocrinol 2010; 325(1-2): 93-100.
[http://dx.doi.org/10.1016/j.mce.2010.04.018] [PMID: 20417686]
[18]
Rivera-Gonzalez GC, Shook BA, Andrae J, et al. Skin Adipocyte Stem Cell Self-Renewal Is Regulated by a PDGFA/AKT-Signaling Axis. Cell Stem Cell 2016; 19(6): 738-51.
[http://dx.doi.org/10.1016/j.stem.2016.09.002] [PMID: 27746098]
[19]
Rodgers SJ, Ferguson DT, Mitchell CA, Ooms LM. Regulation of PI3K effector signalling in cancer by the phosphoinositide phosphatases. Biosci Rep 2017; 37(1) BSR20160432
[http://dx.doi.org/10.1042/BSR20160432] [PMID: 28082369]
[20]
Carnero A, Paramio JM. The PTEN/PI3K/AKT Pathway in vivo, Cancer Mouse Models. Front Oncol 2014; 4: 252.
[http://dx.doi.org/10.3389/fonc.2014.00252] [PMID: 25295225]
[21]
Blanco-Aparicio C, Renner O, Leal JFM, Carnero A. PTEN, more than the AKT pathway. Carcinogenesis 2007; 28(7): 1379-86.
[http://dx.doi.org/10.1093/carcin/bgm052] [PMID: 17341655]
[22]
Song G, Ouyang G, Bao S. The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 2005; 9(1): 59-71.
[http://dx.doi.org/10.1111/j.1582-4934.2005.tb00337.x] [PMID: 15784165]
[23]
Law NC, White MF, Hunzicker-Dunn ME. G protein-coupled receptors (GPCRs) that signal via protein kinase a (pka) cross-talk at insulin receptor substrate 1 (irs1) to activate the phosphatidylinositol 3-kinase (pi3k)/akt pathway. J Biol Chem 2016; 291(53): 27160-9.
[http://dx.doi.org/10.1074/jbc.M116.763235] [PMID: 27856640]
[24]
Phadngam S, Castiglioni A, Ferraresi A, Morani F, Follo C, Isidoro C. PTEN dephosphorylates AKT to prevent the expression of GLUT1 on plasmamembrane and to limit glucose consumption in cancer cells. Oncotarget 2016; 7(51): 84999-5020.
[http://dx.doi.org/10.18632/oncotarget.13113] [PMID: 27829222]
[25]
Linnerth-Petrik NM, Santry LA, Moorehead R, Jücker M, Wootton SK, Petrik J. Akt isoform specific effects in ovarian cancer progression. Oncotarget 2016; 7(46): 74820-33.
[http://dx.doi.org/10.18632/oncotarget.11204] [PMID: 27533079]
[26]
Schenone S, Brullo C, Musumeci F, Radi M, Botta M. ATP-competitive inhibitors of mTOR: an update. Curr Med Chem 2011; 18(20): 2995-3014.
[http://dx.doi.org/10.2174/092986711796391651] [PMID: 21651476]
[27]
Paquette M, El-Houjeiri L, Pause A. mTOR Pathways in Cancer and Autophagy. Cancers (Basel) 2018; 10(1): 18.
[http://dx.doi.org/10.3390/cancers10010018] [PMID: 29329237]
[28]
Pópulo H, Lopes JM, Soares P. The mTOR signalling pathway in human cancer. Int J Mol Sci 2012; 13(2): 1886-918.
[http://dx.doi.org/10.3390/ijms13021886] [PMID: 22408430]
[29]
Rabanal-Ruiz Y, Otten EG, Korolchuk VI. mTORC1 as the main gateway to autophagy. Essays Biochem 2017; 61(6): 565-84.
[http://dx.doi.org/10.1042/EBC20170027] [PMID: 29233869]
[30]
Peterson TR, Laplante M, Thoreen CC, et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 2009; 137(5): 873-86.
[http://dx.doi.org/10.1016/j.cell.2009.03.046] [PMID: 19446321]
[31]
Catena V, Fanciulli M. Deptor: not only a mTOR inhibitor. Journal of experimental & clinical cancer research. CR (East Lansing Mich) 2017; 36(1): 12.
[32]
Martin KR, Zhou W, Bowman MJ, et al. The genomic landscape of tuberous sclerosis complex. Nat Commun 2017; 8: 15816.
[http://dx.doi.org/10.1038/ncomms15816] [PMID: 28643795]
[33]
Takai M, Nakagawa T, Tanabe A, Terai Y, Ohmichi M, Asahi M. Crosstalk between PI3K and Ras pathways via protein phosphatase 2A in human ovarian clear cell carcinoma. Cancer Biol Ther 2015; 16(2): 325-35.
[http://dx.doi.org/10.1080/15384047.2014.1002362] [PMID: 25756515]
[34]
Chiu H-C, Li C-J, Yiang G-T, Tsai AP-Y, Wu M-Y. Epithelial to mesenchymal transition and cell biology of molecular regulation in endometrial carcinogenesis. J Clin Med 2019; 8(4): 439.
[http://dx.doi.org/10.3390/jcm8040439] [PMID: 30935077]
[35]
Kandoth C, Schultz N, Cherniack AD, et al. Integrated genomic characterization of endometrial carcinoma. Nature 2013; 497(7447): 67-73.
[http://dx.doi.org/10.1038/nature12113] [PMID: 23636398]
[36]
Gagnon V, Van Themsche C, Turner S, Leblanc V, Asselin E. Akt and XIAP regulate the sensitivity of human uterine cancer cells to cisplatin, doxorubicin and taxol. Apoptosis 2008; 13(2): 259-71.
[http://dx.doi.org/10.1007/s10495-007-0165-6] [PMID: 18071906]
[37]
Girouard J, Lafleur MJ, Parent S, Leblanc V, Asselin E. Involvement of Akt isoforms in chemoresistance of endometrial carcinoma cells. Gynecol Oncol 2013; 128(2): 335-43.
[http://dx.doi.org/10.1016/j.ygyno.2012.11.016] [PMID: 23174537]
[38]
Chen J, Zhao KN, Li R, Shao R, Chen C. Activation of PI3K/Akt/mTOR pathway and dual inhibitors of PI3K and mTOR in endometrial cancer. Curr Med Chem 2014; 21(26): 3070-80.
[http://dx.doi.org/10.2174/0929867321666140414095605] [PMID: 24735369]
[39]
Tsoref D, Welch S, Lau S, et al. Phase II study of oral ridaforolimus in women with recurrent or metastatic endometrial cancer. Gynecol Oncol 2014; 135(2): 184-9.
[http://dx.doi.org/10.1016/j.ygyno.2014.06.033] [PMID: 25173583]
[40]
Slomovitz BM, Lu KH, Johnston T, et al. A phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma. Cancer 2010; 116(23): 5415-9.
[http://dx.doi.org/10.1002/cncr.25515] [PMID: 20681032]
[41]
Oza AM, Elit L, Tsao MS, et al. Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. J Clin Oncol 2011; 29(24): 3278-85.
[http://dx.doi.org/10.1200/JCO.2010.34.1578] [PMID: 21788564]
[42]
Schwartz LH, Litière S, de Vries E, et al. RECIST 1.1-Update and clarification: From the RECIST committee. Eur J Cancer 2016; 62: 132-7.
[http://dx.doi.org/10.1016/j.ejca.2016.03.081] [PMID: 27189322]
[43]
Morice P, Leary A, Creutzberg C, Abu-Rustum N, Darai E. Endometrial cancer. Lancet 2016; 387(10023): 1094-108.
[http://dx.doi.org/10.1016/S0140-6736(15)00130-0] [PMID: 26354523]
[44]
Mitamura T, Dong P, Ihira K, Kudo M, Watari H. Molecular targeted therapies and precision medicine for endometrial cancer. Jpn J Clin Oncol 2019; 49(2): 108-20.
[http://dx.doi.org/10.1093/jjco/hyy159] [PMID: 30423148]
[45]
Alvarez EA, Brady WE, Walker JL, et al. Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2013; 129(1): 22-7.
[http://dx.doi.org/10.1016/j.ygyno.2012.12.022] [PMID: 23262204]
[46]
Slomovitz BM, Jiang Y, Yates MS, et al. Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma. J Clin Oncol 2015; 33(8): 930-6.
[http://dx.doi.org/10.1200/JCO.2014.58.3401] [PMID: 25624430]
[47]
Hanna RK, Zhou C, Malloy KM, et al. Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway. Gynecol Oncol 2012; 125(2): 458-69.
[http://dx.doi.org/10.1016/j.ygyno.2012.01.009] [PMID: 22252099]
[48]
Fleming GF, Filiaci VL, Marzullo B, et al. Temsirolimus with or without megestrol acetate and tamoxifen for endometrial cancer: a gynecologic oncology group study. Gynecol Oncol 2014; 132(3): 585-92.
[http://dx.doi.org/10.1016/j.ygyno.2014.01.015] [PMID: 24456823]
[49]
Aghajanian C, Filiaci V, Dizon DS, et al. A phase II study of frontline paclitaxel/carboplatin/bevacizumab, paclitaxel/carboplatin/temsirolimus, or ixabepilone/carboplatin/bevacizumab in advanced/recurrent endometrial cancer. Gynecol Oncol 2018; 150(2): 274-81.
[http://dx.doi.org/10.1016/j.ygyno.2018.05.018] [PMID: 29804638]
[50]
Heudel PE, Fabbro M, Roemer-Becuwe C, et al. Phase II study of the PI3K inhibitor BKM120 in patients with advanced or recurrent endometrial carcinoma: a stratified type I-type II study from the GINECO group. Br J Cancer 2017; 116(3): 303-9.
[http://dx.doi.org/10.1038/bjc.2016.430] [PMID: 28072765]
[51]
Matulonis U, Vergote I, Backes F, et al. Phase II study of the PI3K inhibitor pilaralisib (SAR245408; XL147) in patients with advanced or recurrent endometrial carcinoma. Gynecol Oncol 2015; 136(2): 246-53.
[http://dx.doi.org/10.1016/j.ygyno.2014.12.019] [PMID: 25528496]
[52]
Patnaik A, Appleman LJ, Tolcher AW, et al. First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin’s lymphomas. Ann Oncol 2016; 27(10): 1928-40.
[http://dx.doi.org/10.1093/annonc/mdw282] [PMID: 27672108]
[53]
Juric D, Rodon J, Tabernero J, et al. Phosphatidylinositol 3-kinase α-selective inhibition with alpelisib (byl719) in pik3ca-altered solid tumors: results from the first-in-human study. J Clin Oncol 2018; 36(13): 1291-9.
[http://dx.doi.org/10.1200/JCO.2017.72.7107] [PMID: 29401002]
[54]
Mateo J, Ganji G, Lemech C, et al. A first-time-in-human study of gsk2636771, a phosphoinositide 3 kinase beta-selective inhibitor, in patients with advanced solid tumors. Clin Cancer Res 2017; 23(19): 5981-92.
[http://dx.doi.org/10.1158/1078-0432.CCR-17-0725] [PMID: 28645941]
[55]
Makker V, Recio FO, Ma L, et al. A multicenter, single-arm, open label, phase 2 study of apitolisib (GDC-0980) for the treatment of recurrent or persistent endometrial carcinoma (MAGGIE study). Cancer 2016; 122(22): 3519-28.
[http://dx.doi.org/10.1002/cncr.30286] [PMID: 27603005]
[56]
Wise-Draper TM, Moorthy G, Salkeni MA, et al. A phase ib study of the dual pi3k/mtor inhibitor dactolisib (bez235) combined with everolimus in patients with advanced solid malignancies. Target Oncol 2017; 12(3): 323-32.
[http://dx.doi.org/10.1007/s11523-017-0482-9] [PMID: 28357727]
[57]
Del Campo JM, Birrer M, Davis C, et al. A randomized phase II non-comparative study of PF-04691502 and gedatolisib (PF-05212384) in patients with recurrent endometrial cancer. Gynecol Oncol 2016; 142(1): 62-9.
[http://dx.doi.org/10.1016/j.ygyno.2016.04.019] [PMID: 27103175]
[58]
Myers AP, Broaddus R, Makker V, Konstantinopoulos PA, Drapkin R, Horowitz NS, et al. The mTOR signalling pathway in human cancer. Int J of Mol Sci 2013; 13(2): 1886-918.
[59]
Aghajanian C, Bell-McGuinn KM, Burris HA III, et al. A phase I, open-label, two-stage study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the oral AKT inhibitor GSK2141795 in patients with solid tumors. Invest New Drugs 2018; 36(6): 1016-25.
[http://dx.doi.org/10.1007/s10637-018-0591-z] [PMID: 29611022]
[60]
Jansen VM, Mayer IA, Arteaga CL. Is there a future for akt inhibitors in the treatment of cancer? CCR 2016; 22(11): 2599-601.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-0100]
[61]
Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004; 304(5670): 554.
[http://dx.doi.org/10.1126/science.1096502] [PMID: 15016963]
[62]
Musa F, Schneider R. Targeting the PI3K/AKT/mTOR pathway in ovarian cancer. Transl Cancer Res 2015; 4(1): 97-106.
[63]
Berger AC, Korkut A, Kanchi RS, et al. A comprehensive pan cancer molecular study of gynecologic and breast cancers. Cancer Cell 2018; 33(4): 690-705.e9.
[http://dx.doi.org/10.1016/j.ccell.2018.03.014] [PMID: 29622464]
[64]
Rodriguez-Freixinos V, Ruiz-Pace F, Fariñas-Madrid L, et al. Genomic heterogeneity and efficacy of PI3K pathway inhibitors in patients with gynaecological cancer. ESMO Open 2019; 4(2) e000444
[http://dx.doi.org/10.1136/esmoopen-2018-000444] [PMID: 30962959]
[65]
Eskander RN, Tewari KS. Exploiting the therapeutic potential of the PI3K-AKT-mTOR pathway in enriched populations of gynecologic malignancies. Expert Rev Clin Pharmacol 2014; 7(6): 847-58.
[http://dx.doi.org/10.1586/17512433.2014.968554] [PMID: 25301678]
[66]
Cheaib B, Auguste A, Leary A. The PI3K/Akt/mTOR pathway in ovarian cancer: therapeutic opportunities and challenges. Chin J Cancer 2015; 34(1): 4-16.
[http://dx.doi.org/10.5732/cjc.014.10289] [PMID: 25556614]
[67]
De Marco C, Rinaldo N, Bruni P, Malzoni C, Zullo F, Fabiani F, et al. Multiple genetic alterations within the PI3K pathway are responsible for AKT activation in patients with ovarian carcinoma. PloS one 2013; 8(2): e55362-.
[68]
Hauke J, Hahnen E, Schneider S, Reuss A, Richters L, Kommoss S, et al. Deleterious somatic variants in 473 consecutive individuals with ovarian cancer: results of the observational AGO-TR1 study (NCT02222883). Journal of Medical Genetics 2019. jmedgenet-2018-105930.
[69]
Mazzoletti M, Broggini M. PI3K/AKT/mTOR inhibitors in ovarian cancer. Curr Med Chem 2010; 17(36): 4433-47.
[http://dx.doi.org/10.2174/092986710794182999] [PMID: 21062259]
[70]
Huang J, Zhang L, Greshock J, et al. Frequent genetic abnormalities of the PI3K/AKT pathway in primary ovarian cancer predict patient outcome. Genes Chromosomes Cancer 2011; 50(8): 606-18.
[http://dx.doi.org/10.1002/gcc.20883] [PMID: 21563232]
[71]
Tong M, Yu C, Zhan D, et al. Molecular subtyping of cancer and nomination of kinase candidates for inhibition with phosphoproteomics: Reanalysis of CPTAC ovarian cancer. EBioMedicine 2019; 40: 305-17.
[http://dx.doi.org/10.1016/j.ebiom.2018.12.039] [PMID: 30594550]
[72]
Etemadmoghadam D, Bowtell D. AKT1 gene amplification as a biomarker of treatment response in ovarian cancer: mounting evidence of a therapeutic target. Gynecol Oncol 2014; 135(3): 409-10.
[http://dx.doi.org/10.1016/j.ygyno.2014.11.007] [PMID: 25498304]
[73]
Huang H-N, Huang W-C, Lin C-H, Chiang Y-C, Huang H-Y, Kuo K-T. Chromosome 20q13.2 ZNF217 locus amplification correlates with decreased E-cadherin expression in ovarian clear cell carcinoma with PI3K-Akt pathway alterations. Hum Pathol 2014; 45(11): 2318-25.
[http://dx.doi.org/10.1016/j.humpath.2014.07.020] [PMID: 25281027]
[74]
Xin Q, Muer A. Girinimbine Inhibits the Proliferation of Human Ovarian Cancer Cells In Vitro via the Phosphatidylinositol-3-Kinase (PI3K)/Akt and the Mammalian Target of Rapamycin (mTOR) and Wnt/β-Catenin Signaling Pathways. Med Sci Monit 2018; 24: 5480-7.
[http://dx.doi.org/10.12659/MSM.910137] [PMID: 30084434]
[75]
Oishi T, Itamochi H, Kudoh A, et al. The PI3K/mTOR dual inhibitor NVP-BEZ235 reduces the growth of ovarian clear cell carcinoma. Oncol Rep 2014; 32(2): 553-8.
[http://dx.doi.org/10.3892/or.2014.3268] [PMID: 24927217]
[76]
Mukhopadhyay A, Drew Y, Matheson E, Salehan M, Gentles L, Pachter JA, et al. Evaluating the potential of kinase inhibitors to suppress DNA repair and sensitise ovarian cancer cells to PARP inhibitors. Biochem Pharmacol 2018.
[PMID: 30342021]
[77]
David-West G, Ernlund A, Gadi A, Schneider RJ. mTORC1/2 inhibition re-sensitizes platinum-resistant ovarian cancer by disrupting selective translation of DNA damage and survival mRNAs. Oncotarget 2018; 9(69): 33064-76.
[http://dx.doi.org/10.18632/oncotarget.25869] [PMID: 30237852]
[78]
Anne L. An Open-Label Phase I/II Study of GSK2110183 in Combination With Carboplatin and Paclitaxel in Subjects With Platinum Resistant Ovarian Cancer Clinicaltrialsgov ID: NCT01653912
[79]
Fu S, Hennessy BT, Ng CS, et al. Perifosine plus docetaxel in patients with platinum and taxane resistant or refractory high-grade epithelial ovarian cancer. Gynecol Oncol 2012; 126(1): 47-53.
[http://dx.doi.org/10.1016/j.ygyno.2012.04.006] [PMID: 22487539]
[80]
Michalarea V, Roda D, Drew Y, Carreira S, O’Carrigan BS, Shaw H, et al. Abstract CT010: Phase I trial combining the PARP inhibitor olaparib (Ola) and AKT inhibitor AZD5363 (AZD) in germline (g)BRCA and non-BRCA mutant (m) advanced cancer patients (pts) incorporating noninvasive monitoring of cancer mutations. Cancer Res 2016; 76(14)(Suppl.): CT010. [-CT.].
[81]
Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature 2012; 490(7418): 61-70.
[http://dx.doi.org/10.1038/nature11412] [PMID: 23000897]
[82]
Wang ZC, Birkbak NJ, Culhane AC, et al. Profiles of genomic instability in high-grade serous ovarian cancer predict treatment outcome. Clin Cancer Res 2012; 18(20): 5806-15.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-0857] [PMID: 22912389]
[83]
Begg CB, Rice MS, Zabor EC, Tworoger SS. Examining the common aetiology of serous ovarian cancers and basal-like breast cancers using double primaries. Br J Cancer 2017; 116(8): 1088-91.
[http://dx.doi.org/10.1038/bjc.2017.73] [PMID: 28334730]
[84]
Lin J, Sampath D, Nannini MA, et al. Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models. Clin Cancer Res 2013; 19(7): 1760-72.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-3072] [PMID: 23287563]
[85]
Peng W, Chen JQ, Liu C, et al. Loss of PTEN promotes resistance to t cell-mediated immunotherapy. Cancer Discov 2016; 6(2): 202-16.
[http://dx.doi.org/10.1158/2159-8290.CD-15-0283] [PMID: 26645196]
[86]
Kim S-B, Dent R, Im SA, et al. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 2017; 18(10): 1360-72.
[http://dx.doi.org/10.1016/S1470-2045(17)30450-3] [PMID: 28800861]
[87]
Schmid P, Loirat D, Savas P, Espinosa E, Boni V, Italiano A, et al. Abstract CT049: Phase Ib study evaluating a triplet combination of ipatasertib (IPAT), atezolizumab (atezo), and paclitaxel (PAC) or nab-PAC as first-line (1L) therapy for locally advanced/metastatic triple-negative breast cancer (TNBC). Cancer Res 2019; 79(13)(Suppl.): CT049. [-CT.].
[88]
Behbakht K, Sill MW, Darcy KM, et al. Phase II trial of the mTOR inhibitor, temsirolimus and evaluation of circulating tumor cells and tumor biomarkers in persistent and recurrent epithelial ovarian and primary peritoneal malignancies: a Gynecologic Oncology Group study. Gynecol Oncol 2011; 123(1): 19-26.
[http://dx.doi.org/10.1016/j.ygyno.2011.06.022] [PMID: 21752435]
[89]
Campone M, Levy V, Bourbouloux E, et al. Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours. Br J Cancer 2009; 100(2): 315-21.
[http://dx.doi.org/10.1038/sj.bjc.6604851] [PMID: 19127256]
[90]
Boers-Sonderen MJ, de Geus-Oei L-F, Desar IME, et al. Temsirolimus and pegylated liposomal doxorubicin (PLD) combination therapy in breast, endometrial, and ovarian cancer: phase Ib results and prediction of clinical outcome with FDG-PET/CT. Target Oncol 2014; 9(4): 339-47.
[http://dx.doi.org/10.1007/s11523-014-0309-x] [PMID: 24577626]
[91]
Temkin SM, Yamada SD, Fleming GF. A phase I study of weekly temsirolimus and topotecan in the treatment of advanced and/or recurrent gynecologic malignancies. Gynecol Oncol 2010; 117(3): 473-6.
[http://dx.doi.org/10.1016/j.ygyno.2010.02.022] [PMID: 20347480]
[92]
Farley JH, Brady WE, Fujiwara K, Nomura H, Yunokawa M, Tokunaga H, et al. A phase II evaluation of temsirolimus in combination with carboplatin and paclitaxel followed by temsirolimus consolidation as first-line therapy in the treatment of stage III-IV clear cell carcinoma of the ovary. Journal of Clinical Oncology 2016; 34(15_suppl): 5531.
[http://dx.doi.org/10.1200/JCO.2016.34.15_suppl.5531]
[93]
Tew WP, Sill MW, Walker JL, et al. Randomized phase II trial of bevacizumab plus everolimus versus bevacizumab alone for recurrent or persistent ovarian, fallopian tube or peritoneal carcinoma: An NRG oncology/gynecologic oncology group study. Gynecol Oncol 2018; 151(2): 257-63.
[http://dx.doi.org/10.1016/j.ygyno.2018.08.027] [PMID: 30177462]
[94]
Merker JD, Oxnard GR, Compton C, et al. Circulating tumor dna analysis in patients with cancer: american society of clinical oncology and college of american pathologists joint review. J Clin Oncol 2018; 36(16): 1631-41.
[http://dx.doi.org/10.1200/JCO.2017.76.8671] [PMID: 29504847]
[95]
Di Leo A, Johnston S, Lee KS, et al. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo controlled, phase 3 trial. Lancet Oncol 2018; 19(1): 87-100.
[http://dx.doi.org/10.1016/S1470-2045(17)30688-5] [PMID: 29223745]
[96]
Gampenrieder SP, Rinnerthaler G, Greil R. SABCS 2016: systemic therapy for metastatic breast cancer. Memo 2017; 10(2): 86-9.
[http://dx.doi.org/10.1007/s12254-017-0326-4] [PMID: 28725277]
[97]
Murtaza M, Dawson S-J, Tsui DWY, et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 2013; 497(7447): 108-12.
[http://dx.doi.org/10.1038/nature12065] [PMID: 23563269]
[98]
Bolivar AM, Luthra R, Mehrotra M, et al. Targeted next-generation sequencing of endometrial cancer and matched circulating tumor DNA: identification of plasma-based, tumor-associated mutations in early stage patients. Mod Pathol 2019; 32(3): 405-14.
[http://dx.doi.org/10.1038/s41379-018-0158-8] [PMID: 30315273]
[99]
Alonso-Alconada L, Muinelo-Romay L, Madissoo K, et al. Molecular profiling of circulating tumor cells links plasticity to the metastatic process in endometrial cancer. Mol Cancer 2014; 13: 223.
[http://dx.doi.org/10.1186/1476-4598-13-223] [PMID: 25261936]
[100]
Iwahashi N, Sakai K, Noguchi T, et al. Liquid biopsy-based comprehensive gene mutation profiling for gynecological cancer using CAncer Personalized Profiling by deep Sequencing. Sci Rep 2019; 9(1): 10426.
[http://dx.doi.org/10.1038/s41598-019-47030-w] [PMID: 31320709]
[101]
Du Z-H, Bi F-F, Wang L, Yang Q. Next-generation sequencing unravels extensive genetic alteration in recurrent ovarian cancer and unique genetic changes in drug-resistant recurrent ovarian cancer. Mol Genet Genomic Med 2018; 6(4): 638-47.
[http://dx.doi.org/10.1002/mgg3.414] [PMID: 29797793]
[102]
Ross JS, Ali SM, Wang K, et al. Comprehensive genomic profiling of epithelial ovarian cancer by next generation sequencing-based diagnostic assay reveals new routes to targeted therapies. Gynecol Oncol 2013; 130(3): 554-9.
[http://dx.doi.org/10.1016/j.ygyno.2013.06.019] [PMID: 23791828]
[103]
Rojas V, Hirshfield KM, Ganesan S, Rodriguez-Rodriguez L. Molecular Characterization of Epithelial Ovarian Cancer: Implications for Diagnosis and Treatment. Int J Mol Sci 2016; 17(12): 2113.
[http://dx.doi.org/10.3390/ijms17122113] [PMID: 27983698]
[104]
Salazar C, Campbell IG, Gorringe KL. When Is “Type I” Ovarian Cancer Not “Type I”? Indications of an Out-Dated Dichotomy. Front Oncol 2018; 8(654): 654.
[http://dx.doi.org/10.3389/fonc.2018.00654] [PMID: 30627526]
[105]
Talhouk A, McAlpine JN. New classification of endometrial cancers: the development and potential applications of genomic-based classification in research and clinical care. Gynecol Oncol Res Pract 2016; 3: 14.
[http://dx.doi.org/10.1186/s40661-016-0035-4] [PMID: 27999680]
[106]
McAlpine J, Leon-Castillo A, Bosse T. The rise of a novel classification system for endometrial carcinoma; integration of molecular subclasses. J Pathol 2018; 244(5): 538-49.
[http://dx.doi.org/10.1002/path.5034] [PMID: 29344951]
[107]
Guan L-Y, Lu Y. New developments in molecular targeted therapy of ovarian cancer. Discov Med 2018; 26(144): 219-29.
[PMID: 30695681]
[108]
Barra F, Evangelisti G, Ferro Desideri L, et al. Investigational PI3K/AKT/mTOR inhibitors in development for endometrial cancer. Expert Opin Investig Drugs 2019; 28(2): 131-42.
[http://dx.doi.org/10.1080/13543784.2018.1558202] [PMID: 30574817]
[109]
Ali AY, Kim J-Y, Pelletier J-F, Vanderhyden BC, Bachvarov DR, Tsang BK. Akt confers cisplatin chemoresistance in human gynecological carcinoma cells by modulating PPM1D stability. Mol Carcinog 2015; 54(11): 1301-14.
[http://dx.doi.org/10.1002/mc.22205] [PMID: 25154814]
[110]
Fan Y, Wang L, Han X, Liu X, Ma H. Rab25 is responsible for phosphoinositide 3-kinase/AKT‑mediated cisplatin resistance in human epithelial ovarian cancer cells. Mol Med Rep 2015; 11(3): 2173-8.
[http://dx.doi.org/10.3892/mmr.2014.2963] [PMID: 25405658]
[111]
Hahne JC, Honig A, Meyer SR, et al. Downregulation of AKT reverses platinum resistance of human ovarian cancers in vitro. Oncol Rep 2012; 28(6): 2023-8.
[http://dx.doi.org/10.3892/or.2012.2041] [PMID: 22992944]
[112]
Choi HJ, Heo JH, Park JY, et al. A novel PI3K/mTOR dual inhibitor, CMG002, overcomes the chemoresistance in ovarian cancer. Gynecol Oncol 2019; 153(1): 135-48.
[http://dx.doi.org/10.1016/j.ygyno.2019.01.012] [PMID: 30686552]
[113]
Li X, Dai D, Chen B, Tang H, Xie X, Wei W. Efficacy of PI3K/AKT/mTOR pathway inhibitors for the treatment of advanced solid cancers: A literature-based meta-analysis of 46 randomised control trials. PloS one 2018; 13(2): e0192464-.
[114]
Rugo HS, Seneviratne L, Beck JT, et al. Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial. Lancet Oncol 2017; 18(5): 654-62.
[http://dx.doi.org/10.1016/S1470-2045(17)30109-2] [PMID: 28314691]
[115]
André F, O’Regan R, Ozguroglu M, et al. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 2014; 15(6): 580-91.
[http://dx.doi.org/10.1016/S1470-2045(14)70138-X] [PMID: 24742739]
[116]
Vuylsteke P, Huizing M, Petrakova K, et al. Pictilisib PI3Kinase inhibitor (a phosphatidylinositol 3-kinase [PI3K] inhibitor) plus paclitaxel for the treatment of hormone receptor-positive, HER2-negative, locally recurrent, or metastatic breast cancer: interim analysis of the multicentre, placebo-controlled, phase II randomised PEGGY study. Ann Oncol 2016; 27(11): 2059-66.
[http://dx.doi.org/10.1093/annonc/mdw320] [PMID: 27573562]
[117]
Blagden SP, Hamilton AL, Mileshkin L, et al. Phase IB Dose Escalation and Expansion Study of AKT Inhibitor Afuresertib with Carboplatin and Paclitaxel in Recurrent Platinum-resistant Ovarian Cancer. Clin Cancer Res 2019; 25(5): 1472-8.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-2277] [PMID: 30563934]
[118]
Davies C, Pan H, Godwin J, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013; 381(9869): 805-16.
[http://dx.doi.org/10.1016/S0140-6736(12)61963-1] [PMID: 23219286]
[119]
Shang Y, Brown M. Molecular determinants for the tissue specificity of SERMs. Science 2002; 295(5564): 2465-8.
[http://dx.doi.org/10.1126/science.1068537] [PMID: 11923541]
[120]
Paleari L, Gandini S, Provinciali N, Puntoni M, Colombo N, De-Censi A. Clinical benefit and risk of death with endocrine therapy in ovarian cancer: A comprehensive review and meta-analysis. Gynecol Oncol 2017; 146(3): 504-13.
[http://dx.doi.org/10.1016/j.ygyno.2017.06.036] [PMID: 28705409]
[121]
Heinzelmann-Schwarz V, Knipprath Mészaros A, Stadlmann S, et al. Letrozole may be a valuable maintenance treatment in high grade serous ovarian cancer patients. Gynecol Oncol 2018; 148(1): 79-85.
[http://dx.doi.org/10.1016/j.ygyno.2017.10.036] [PMID: 29157627]
[122]
Dosil MA, Mirantes C, Eritja N, et al. Palbociclib has antitumour effects on Pten-deficient endometrial neoplasias. J Pathol 2017; 242(2): 152-64.
[http://dx.doi.org/10.1002/path.4896] [PMID: 28349562]
[123]
Chae YK, Anker JF, Carneiro BA, et al. Genomic landscape of DNA repair genes in cancer. Oncotarget 2016; 7(17): 23312-21.
[http://dx.doi.org/10.18632/oncotarget.8196] [PMID: 27004405]
[124]
Konstantinopoulos PA, Barry WT, Birrer M, et al. Olaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial. Lancet Oncol 2019; 20(4): 570-80.
[http://dx.doi.org/10.1016/S1470-2045(18)30905-7] [PMID: 30880072]
[125]
Monk BJ, Minion LE, Coleman RL. Anti-angiogenic agents in ovarian cancer: past, present, and future. Annals of oncology : official journal of the European Society for Medical Oncology 2016; 27 Suppl 1(Suppl 1): i33-9.
[http://dx.doi.org/10.1093/annonc/mdw093]
[126]
Soler A, Angulo-Urarte A, Graupera M. PI3K at the crossroads of tumor angiogenesis signaling pathways. Molecular & cellular oncology 2015; 2(2): e975624-.
[127]
Fruman DA, Rommel C. PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov 2014; 13(2): 140-56.
[http://dx.doi.org/10.1038/nrd4204] [PMID: 24481312]
[128]
Luo H, Xu X, Ye M, Sheng B, Zhu X. The prognostic value of HER2 in ovarian cancer: A meta-analysis of observational studies. PloS one 2018; 13(1): e0191972-.
[http://dx.doi.org/10.1371/journal.pone.0191972]
[129]
Diver EJ, Foster R, Rueda BR, Growdon WB. The therapeutic challenge of targeting her2 in endometrial cancer. Oncologist 2015; 20(9): 1058-68.
[http://dx.doi.org/10.1634/theoncologist.2015-0149] [PMID: 26099744]
[130]
Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2(2): 127-37.
[http://dx.doi.org/10.1038/35052073] [PMID: 11252954]
[131]
Bonazzoli E, Cocco E, Lopez S, et al. PI3K oncogenic mutations mediate resistance to afatinib in HER2/neu overexpressing gynecological cancers. Gynecol Oncol 2019; 153(1): 158-64.
[http://dx.doi.org/10.1016/j.ygyno.2019.01.002] [PMID: 30630630]
[132]
Urpilainen E, Marttila M, Hautakoski A, et al. Prognosis of ovarian cancer in women with type 2 diabetes using metformin and other forms of antidiabetic medication or statins: a retrospective cohort study. BMC Cancer 2018; 18(1): 767.
[http://dx.doi.org/10.1186/s12885-018-4676-z] [PMID: 30055585]
[133]
Trabert B, Wentzensen N, Felix AS, Yang HP, Sherman ME, Brinton LA. Metabolic syndrome and risk of endometrial cancer in the united states: a study in the SEER-medicare linked database. Cancer Epidemiol Biomarkers Prev 2015; 24(1): 261-7.
[http://dx.doi.org/10.1158/1055-9965.EPI-14-0923] [PMID: 25587111]
[134]
Qiang P, Shao Y, Sun YP, Zhang J, Chen LJ. Metformin inhibits proliferation and migration of endometrial cancer cells through regulating PI3K/AKT/MDM2 pathway. Eur Rev Med Pharmacol Sci 2019; 23(4): 1778-85.
[PMID: 30840303]
[135]
Schuler KM, Rambally BS, DiFurio MJ, et al. Antiproliferative and metabolic effects of metformin in a preoperative window clinical trial for endometrial cancer. Cancer Med 2015; 4(2): 161-73.
[http://dx.doi.org/10.1002/cam4.353] [PMID: 25417601]
[136]
Hopkins BD, Pauli C, Du X, et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 2018; 560(7719): 499-503.
[http://dx.doi.org/10.1038/s41586-018-0343-4] [PMID: 30051890]
[137]
O’Donnell JS, Massi D, Teng MWL, Mandala M. PI3K-AKT mTOR inhibition in cancer immunotherapy, redux. Semin Cancer Biol 2018; 48: 91-103.
[http://dx.doi.org/10.1016/j.semcancer.2017.04.015] [PMID: 28467889]
[138]
Gato-Cañas M, Martinez de Morentin X, Blanco-Luquin I, et al. A core of kinase-regulated interactomes defines the neoplastic MDSC lineage. Oncotarget 2015; 6(29): 27160-75.
[http://dx.doi.org/10.18632/oncotarget.4746] [PMID: 26320174]
[139]
Abu-Eid R, Samara RN, Ozbun L, et al. Selective inhibition of regulatory T cells by targeting the PI3K-Akt pathway. Cancer Immunol Res 2014; 2(11): 1080-9.
[http://dx.doi.org/10.1158/2326-6066.CIR-14-0095] [PMID: 25080445]
[140]
Chellappa S, Kushekhar K, Munthe LA, et al. The PI3K p110δ Isoform Inhibitor Idelalisib Preferentially Inhibits Human Regulatory T Cell Function. J Immunol 2019; 202(5): 1397-405.
[http://dx.doi.org/10.4049/jimmunol.1701703] [PMID: 30692213]


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VOLUME: 21
ISSUE: 10
Year: 2020
Published on: 20 November, 2019
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DOI: 10.2174/1389450120666191120123612
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