The PI3K/Akt/mTOR pathway in ovarian cancer: Therapeutic opportunities and challenges

Chinese Journal of Cancer

Volumn 34, Issue 1, 2015, Pages 4-16

  Cheaib, Bianca ^a   Auguste, Aurélie ^a   Leary, Alexandra ^a  

^a INSTITUT GUSTAVE ROUSSY   (France)

Author keywords

Ovarian cancer; Predictive biomarkers; The PI3K pathway

Indexed keywords

4 [2 (4 AMINO 1,2,5 OXADIAZOL 3 YL) 1 ETHYL 7 (3 PIPERIDINYLMETHOXY) 1H IMIDAZO[4,5 C]PYRIDIN 4 YL] 2 METHYL 3 BUTYN 2 OL; 8 [4 (1 AMINOCYCLOBUTYL)PHENYL] 9 PHENYL 1,2,4 TRIAZOLO[3,4 F][1,6]NAPHTHYRIDIN 3(2H) ONE; AFURESERTIB; B RAF KINASE INHIBITOR; BEVACIZUMAB; BUPARLISIB; CARBOPLATIN; CYCLIN D1; DOCETAXEL; DOXORUBICIN; EVEROLIMUS; GSK 211; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; PACLITAXEL; PANITUMUMAB; PERIFOSINE; PHOSPHATIDYLINOSITOL 3 KINASE; PICTILISIB; PILARALISIB; PROTEIN KINASE B; PROTEIN KINASE B INHIBITOR; PROTEIN P53; RAPAMYCIN; RIDAFOROLIMUS; TEMSIROLIMUS; TOPOTECAN; TRABECTEDIN; UNCLASSIFIED DRUG; UNINDEXED DRUG; UPROSERTIB; ANTINEOPLASTIC AGENT; TARGET OF RAPAMYCIN KINASE;

ANEMIA; ANOREXIA; ARTICLE; BONE MARROW TOXICITY; CELL HETEROGENEITY; DIARRHEA; DNA METHYLATION; FATIGUE; GASTROINTESTINAL TOXICITY; GENE AMPLIFICATION; GENE DOSAGE; GENE EXPRESSION; GRAFT REJECTION; HAND FOOT SYNDROME; HORMONAL THERAPY; HUMAN; HYPERGLYCEMIA; HYPERTENSION; HYPERTRIGLYCERIDEMIA; LUNG TOXICITY; MAXIMUM TOLERATED DOSE; MOOD DISORDER; MUCOSA INFLAMMATION; MUTATION; NAUSEA; NAUSEA AND VOMITING; NEUTROPENIA; OVARY CANCER; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); RASH; SIGNAL TRANSDUCTION; STOMATITIS; THROMBOCYTOPENIA; UNSPECIFIED SIDE EFFECT; VOMITING; ANTAGONISTS AND INHIBITORS; DRUG EFFECTS; DRUG RESISTANCE; FEMALE; OVARIAN NEOPLASMS; PHYSIOLOGY;

ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; DRUG RESISTANCE, NEOPLASM; FEMALE; HUMANS; OVARIAN NEOPLASMS; PHOSPHATIDYLINOSITOL 3-KINASES; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 84920261457     PISSN: None     EISSN: 1944446X     Source Type: Journal    
DOI: 10.5732/cjc.014.10289     Document Type: Article

References (70)

1. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature, 2011,474:609-615.
2. Bowtell DD. The genesis and evolution of high-grade serous ovarian cancer. Nat Rev Cancer, 2010,10:803-808.
3. Kurman RJ, Shih IeM. Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer—shifting the paradigm. Hum Pathol, 2011,42:918-931.
4. Cerami E, Gao J, Dogrusoz U, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov, 2012,2:401-404.
5. Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal, 2013,6:p11.
6. Zorn KK, Bonome T, Gangi L, et al. Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer. Clin Cancer Res, 2005,11:6422-6430.
7. Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene, 2005,24:7455-7464.
8. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer, 2009,9:550-562.
9. Leary A, Lhomme C, Auclin E, et al. The PI3K/Akt/mTOR pathway in ovarian cancer: biological rationale and therapeutic promise. INTECH Open Access Publisher, 2013.
10. Liang J, Slingerland JM. Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle, 2003,2:339-345.
11. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell, 2006,124:471-484.
12. Huang K, Fingar DC. Growing knowledge of the mTOR signaling network. Semin Cell Dev Biol, 2014,36C:79-90.
13. Gibbons JJ, Abraham RT, Yu K. Mammalian target of rapamycin: discovery of rapamycin reveals a signaling pathway important for normal and cancer cell growth. Semin Oncol, 2009,36 Suppl 3:S3-S17.
14. Ballou LM, Lin RZ. Rapamycin and mTOR kinase inhibitors. J Chem Biol, 2008,1:27-36.
15. Shackelford DB, Shaw RJ. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer, 2009,9:563-575.
16. Shaw RJ. LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta Physiol, 2009,196:65-80.
17. 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, 2011,50:606-618.
18. Altomare DA, Wang HQ, Skele KL, et al. AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth. Oncogene, 2004,23:5853-5857.
19. Kato M, Yamamoto S, Takano M, et al. Aberrant expression of the mammalian target of rapamycin, hypoxia-inducible factor-1alpha, and glucose transporter 1 in the development of ovarian clear-cell adenocarcinoma. Int J Gynecol Pathol, 2012,31:254-263.
20. Mabuchi S, Kawase C, Altomare DA, et al. mTOR is a promising therapeutic target both in cisplatin-sensitive and cisplatin-resistant clear cell carcinoma of the ovary. Clin Cancer Res, 2009,15:5404-5413.
21. Romero I, Bast RC Jr. Minireview: human ovarian cancer: biology, current management, and paths to personalizing therapy. Endocrinology, 2012,153:1593-602.
22. Kinross KM, Montgomery KG, Kleinschmidt M, et al. An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice. J Clin Invest, 2012,122:553-557.
23. Tanwar PS, Zhang L, Kaneko-Tarui T, et al. Mammalian target of rapamycin is a therapeutic target for murine ovarian endometrioid adenocarcinomas with dysregulated Wnt/beta-catenin and PTEN. PLoS One, 2011,6:e20715.
24. Dumont FJ, Su Q. Mechanism of action of the immunosuppressant rapamycin. Life Sci, 1996,58:373-395.
25. 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, 2011,123:19-26.
26. Takano M, Kikuchi Y, Kudoh K, et al. Weekly administration of temsirolimus for heavily pretreated patients with clear cell carcinoma of the ovary: a report of six cases. Int J Clin Oncol, 2011,16:605-609.
27. Okamoto A, Glasspool RM, Mabuchi S, et al. Gynecologic Cancer InterGroup (GCIG) Consensus Review for Clear Cell Carcinoma of the Ovary. Int J Gynecol Cancer, 2014,24:S20-S25.
28. 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, 2010,117:473-476.
29. Boers-Sonderen M DI, Van Der Graaf WTA, Ottevanger PB, et al. A phase Ib study of the combination of temsirolimus and pegylated liposomal doxorubcin in advanced or recurrent breast, endometrial and ovarian cancer. J Clin Oncol, 2012,30:Abstr 5061.
30. Kollmannsberger C, Hirte H, Siu LL, et al. Temsirolimus in combination with carboplatin and paclitaxel in patients with advanced solid tumors: a NCIC-CTG, phase I, open-label doseescalation study (IND 179). Ann Oncol, 2012,23:238-244.
31. Chon HJP, Apte S, Lee JH, et al. Phase I study of combination carboplatin, paclitaxel and ridaforolimus in patients with solid, endometrial and ovarian cancers. J Clin Oncol, 2014,32:abstr 2614.
32. 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, 2009,100:315-321.
33. Takano MKH, Ikeda Y, Sasaki N, et al. Combination chemotherapy withh temsirolimus and trabectedin for recurrent clear cell carcinoma of the ovary: a phase II single arm clinical trial. J Clin Oncol, 2014,32: abstr 5517.
34. Sun SY, Rosenberg LM, Wang X, et al. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res, 2005,65:7052-7058.
35. Breuleux M, Klopfenstein M, Stephan C, et al. Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition. Mol Cancer Ther, 2009,8:742-753.
36. Zhang YJ, Duan Y, Zheng XF. Targeting the mTOR kinase domain: the second generation of mTOR inhibitors. Drug Discov Today, 2011,16:325-331.
37. Fu S, Hennessy BT, Ng CS, et al. Perifosine plus docetaxel in patients with platinum and taxane resistant or refractory highgrade epithelial ovarian cancer. Gynecol Oncol, 2012,126:47-53.
38. Gungor H SA, Agarwal R, Blagden S, et al Pharmacokinetic/ pharmacodynamic analysis of escalating repeat doses of the Akt inhibitor GSK795 in patients with ovarian cancer. J Clin Oncol, 2011,29:Abstr 5064.
39. Blagden S, Hamilton A, Mileshkin L, et al. Afuresertib (GSK2110183), an oral AKT inhibitor in combination with carboplatin and paclitaxel in recurrent ovarian cancer. 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, 2014.
40. Gordon AN, Fleagle JT, Guthrie D, et al. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol, 2001,19:3312-3322.
41. Moreno Garcia VBR, Shah KJ, Basu B, et al. A phase I study evaluating GDC-0941, an oral PI3K inhibitor in patients with advanced solid tumors or multiple myeloma. J Clin Oncol, 2011,29:Abstr 3021.
42. Traynor AM KR, Bailey HH, Attia S, et al. A phase I safety and pharmacokinetic study of the PI3K inhibitor XL147 in combination with paclitaxel and carboplatin in patients with advanced solid tumors. J Clin Oncol, 2010,28: Abstr 3078.
43. Neshat MS, Mellinghoff IK, Tran C, et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci U S A, 2001,98:10314-10319.
44. Noh WC, Mondesire WH, Peng J, et al. Determinants of rapamycin sensitivity in breast cancer cells. Clin Cancer Res, 2004,10:1013-1023.
45. Tanaka H, Yoshida M, Tanimura H, et al. The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations. Clin Cancer Res, 2011,17:3272-3281.
46. Di Nicolantonio F, Arena S, Tabernero J, et al. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest, 2010,120:2858-2866.
47. Weigelt B, Warne PH, Downward J. PIK3CA mutation, but not PTEN loss of function, determines the sensitivity of breast cancer cells to mTOR inhibitory drugs. Oncogene, 2011,30:3222-3233.
48. O'Brien C, Wallin JJ, Sampath D, et al. Predictive biomarkers of sensitivity to the phosphatidylinositol 3' kinase inhibitor GDC- 0941 in breast cancer preclinical models. Clin Cancer Res, 2010,16:3670-3683.
49. Mackay HJ, Eisenhauer EA, Kamel-Reid S, et al. Molecular determinants of outcome with mammalian target of rapamycin inhibition in endometrial cancer. Cancer, 2014,120:603-610.
50. Loboda A, Nebozhyn M, Klinghoffer R, et al. A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors. BMC Med Genomics, 2010,3:26.
51. Wan X, Harkavy B, Shen N, et al. Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene, 2007,26:1932-1940.
52. Buck E, Eyzaguirre A, Rosenfeld-Franklin M, et al. Feedback mechanisms promote cooperativity for small molecule inhibitors of epidermal and insulin-like growth factor receptors. Cancer Res, 2008, 68:8322-8332.
53. Kim A, Lee JE, Lee SS, et al. Coexistent mutations of KRAS and PIK3CA affect the efficacy of NVP-BEZ235, a dual PI3K/MTOR inhibitor, in regulating the PI3K/MTOR pathway in colorectal cancer. Int J Cancer, 2013,133:984-996.
54. Carracedo A, Ma L, Teruya-Feldstein J, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest, 2008,118:3065-3074.
55. Mazzoletti M, Bortolin F, Brunelli L, et al. Combination of PI3K/mTOR inhibitors: antitumor activity and molecular correlates. Cancer Res, 2011,71:4573-4584.
56. Vlahovic G, Meadows KL, Uronis HE, et al. A phase I study of bevacizumab, everolimus and panitumumab in advanced solid tumors. Cancer Chemother Pharmacol, 2012,70:95-102.
57. O'Reilly KE, Rojo F, She QB, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res, 2006,66:1500-1508.
58. Quek R, Wang QA, Morgan JA, et al. Combination mTOR and IGF- 1R inhibition: phase I trial of everolimus and figitumumab in patients with advanced sarcomas and other solid tumors. Clin Cancer Res, 2011,17:871-879.
59. Brana I, Berger R, Golan T, et al. A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours. Br J Cancer, 2014, 111:1932-1944.
60. Kinross KM, Brown DV, Kleinschmidt M, et al. In vivo activity of combined PI3K/mTOR and MEK inhibition in a Kras(G12D);Pten deletion mouse model of ovarian cancer. Mol Cancer Ther, 2011,10:1440-1449.
61. Juric JS, Sharma S, Banerji U, et al. A phase IB dose-escalation study of BYL719 plus binimetinib (MEK162) in patients with selected advanced solid tumors. J Clin Oncol, 2014,32: Abstr 9051.
62. Spreafico AO, Clarke B, Mackay H, et al. Gentotype matched treatment for patients with type I epithelial ovarian cancer. J Clin Oncol, 2014,32: Abstr 5506.
63. Anglesio MS, George J, Kulbe H, et al. IL6-STAT3-HIF signaling and therapeutic response to the angiogenesis inhibitor sunitinib in ovarian clear cell cancer. Clin Cancer Res, 2011,17:2538-2548.
64. Morgan R OA, Qin R, Laumann KM, et al. A phase II trial of temsirolimus and bevacizumab in patients with endometrial, ovarian, hepatocellular carcinoma, carcinoid or islet cell cancer: Ovarian cancer subset. J Clin Oncol, 2011,29:Abstr 5015.
65. Burger RA, Sill MW, Monk BJ, et al. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study. J Clin Oncol, 2007,25:5165-5171.
66. Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol, 2007,25:5180-5186.
67. Tew WSM, McMeekin S, Secord A, et al. A randomized phase II trial of bevacizumab plus everolimus versus bevacizumab alone for recurrent or persitent epithelial ovarian cancer. J Clin Oncol, 2014,32: Abstr 5546.
68. Matulonis UWG, Birrer M, Neville S, et al. Phase I study of oral BKM120 and oral olaparib for high grade serous ovarian cancer or triple negative breast cancer. J Clin Oncol, 2014,32: Abstr 2510.
69. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med, 2012,366:520-529.
70. Wheler JJ, Moulder SL, Naing A, et al. Anastrozole and everolimus in advanced gynecologic and breast malignancies: activity and molecular alterations in the PI3K/AKT/mTOR pathway. Oncotarget, 2014,5:3029-3038.