Effectiveness and molecular interactions of the clinically active mTORC1 inhibitor everolimus in combination with tamoxifen or letrozole in vitro and in vivo

Breast Cancer Research

Volumn 14, Issue 5, 2012, Pages

  Martin, Lesley Ann ^a   Pancholi, Sunil ^a   Farmer, Ian ^a   Guest, Stephanie ^a   Ribas, Ricardo ^a   Weigel, Marion T ^a   Thornhill, Allan M ^a   Ghazoui, Zara ^a   A'Hern, Roger ^a   Evans, Dean B ^b   Lane, Heidi A ^b   Johnston, Stephen R ^c   Dowsett, Mitch ^a,c  

^a INSTITUTE OF CANCER RESEARCH   (United Kingdom)

^b NOVARTIS PHARMA AG   (Switzerland)

^c ROYAL MARSDEN HOSPITAL   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

AROMATASE; EPIDERMAL GROWTH FACTOR RECEPTOR 2; EVEROLIMUS; GROWTH FACTOR; LETROZOLE; PROTEIN P27; TAMOXIFEN; ANTINEOPLASTIC HORMONE AGONISTS AND ANTAGONISTS; EPIDERMAL GROWTH FACTOR RECEPTOR 3; ESTROGEN RECEPTOR; MECHANISTIC TARGET OF RAPAMYCIN COMPLEX 1; MULTIPROTEIN COMPLEX; NITRILE; PROTEIN KINASE B; PROTEIN KINASE INHIBITOR; RAPAMYCIN; TARGET OF RAPAMYCIN KINASE; TRIAZOLE DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIPROLIFERATIVE ACTIVITY; ARTICLE; BREAST CANCER; CANCER CELL CULTURE; CELL CYCLE ARREST; CELL PROLIFERATION; CELL STRAIN MCF 7; DRUG EFFICACY; ENDOPLASMIC RETICULUM; HUMAN; IN VITRO STUDY; IN VIVO STUDY; MOUSE; NONHUMAN; PROTEIN DEPHOSPHORYLATION; PROTEIN PHOSPHORYLATION; SIGNAL TRANSDUCTION; TUMOR VOLUME; TUMOR XENOGRAFT; ANALOGS AND DERIVATIVES; ANIMAL; ANTAGONISTS AND INHIBITORS; BREAST NEOPLASMS; CELL CYCLE; DISEASE MODEL; DRUG EFFECTS; DRUG RESISTANCE; DRUG SCREENING; FEMALE; METABOLISM; NUCLEOLUS; PATHOLOGY; PHOSPHORYLATION; PROTEIN TRANSPORT; TUMOR CELL LINE;

ANIMALS; ANTINEOPLASTIC AGENTS, HORMONAL; BREAST NEOPLASMS; CELL CYCLE; CELL LINE, TUMOR; CELL NUCLEOLUS; CELL PROLIFERATION; DISEASE MODELS, ANIMAL; DRUG RESISTANCE, NEOPLASM; FEMALE; HUMANS; MICE; MULTIPROTEIN COMPLEXES; NITRILES; PHOSPHORYLATION; PROTEIN KINASE INHIBITORS; PROTEIN TRANSPORT; PROTO-ONCOGENE PROTEINS C-AKT; RECEPTOR, ERBB-3; RECEPTORS, ESTROGEN; SIGNAL TRANSDUCTION; SIROLIMUS; TAMOXIFEN; TOR SERINE-THREONINE KINASES; TRIAZOLES; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84867441207     PISSN: 14655411     EISSN: 1465542X     Source Type: Journal    
DOI: 10.1186/bcr3330     Document Type: Article

References (48)

1. Ali S, Coombes RC. Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer 2002, 2:101-112. 10.1038/nrc721, 12635173.
2. Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005, 5:341-354. 10.1038/nrc1609, 15864276.
3. Perez-Tenorio G, Stal O. Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients. Br J Cancer 2002, 86:540-545. 10.1038/sj.bjc.6600126, 2375266, 11870534.
4. Stal O, Perez-Tenorio G, Akerberg L, Olsson B, Nordenskjold B, Skoog L, Rutqvist LE. Akt kinases in breast cancer and the results of adjuvant therapy. Breast Cancer Res 2003, 5:R37-44. 10.1186/bcr569, 154147, 12631397.
5. Tokunaga E, Kataoka A, Kimura Y, Oki E, Mashino K, Nishida K, Koga T, Morita M, Kakeji Y, Baba H, et al. The association between Akt activation and resistance to hormone therapy in metastatic breast cancer. Eur J Cancer 2006, 42:629-635. 10.1016/j.ejca.2005.11.025, 16464571.
6. Miller TW, Hennessy BT, Gonzalez-Angulo AM, Fox EM, Mills GB, Chen H, Higham C, Garcia-Echeverria C, Shyr Y, Arteaga CL. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest 2010, 120:2406-2413. 10.1172/JCI41680, 2898598, 20530877.
7. Pancholi S, Lykkesfeldt AE, Hilmi C, Banerjee S, Leary A, Drury S, Johnston S, Dowsett M, Martin LA. ERBB2 influences the subcellular localization of the estrogen receptor in tamoxifen-resistant MCF-7 cells leading to the activation of AKT and RPS6KA2. Endocr Relat Cancer 2008, 15:985-1002. 10.1677/ERC-07-0240, 18824559.
8. Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H. Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J Biol Chem 2001, 276:9817-9824. 10.1074/jbc.M010840200, 11139588.
9. Bhat-Nakshatri P, Wang G, Appaiah H, Luktuke N, Carroll JS, Geistlinger TR, Brown M, Badve S, Liu Y, Nakshatri H. AKT alters genome-wide estrogen receptor alpha binding and impacts estrogen signaling in breast cancer. Mol Cell Biol 2008, 28:7487-7503. 10.1128/MCB.00799-08, 2593438, 18838536.
10. Hashemolhosseini S, Nagamine Y, Morley SJ, Desrivieres S, Mercep L, Ferrari S. Rapamycin inhibition of the G1 to S transition is mediated by effects on cyclin D1 mRNA and protein stability. J Biol Chem 1998, 273:14424-14429. 10.1074/jbc.273.23.14424, 9603954.
11. West MJ, Stoneley M, Willis AE. Translational induction of the c-myc oncogene via activation of the FRAP/TOR signalling pathway. Oncogene 1998, 17:769-780. 10.1038/sj.onc.1201990, 9715279.
12. Nourse J, Firpo E, Flanagan WM, Coats S, Polyak K, Lee MH, Massague J, Crabtree GR, Roberts JM. Interleukin-2-mediated elimination of the p27Kip1 cyclin-dependent kinase inhibitor prevented by rapamycin. Nature 1994, 372:570-573. 10.1038/372570a0, 7990932.
13. Beuvink I, Boulay A, Fumagalli S, Zilbermann F, Ruetz S, O'Reilly T, Natt F, Hall J, Lane HA, Thomas G. The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell 2005, 120:747-759. 10.1016/j.cell.2004.12.040, 15797377.
14. Gingras AC, Raught B, Gygi SP, Niedzwiecka A, Miron M, Burley SK, Polakiewicz RD, Wyslouch-Cieszynska A, Aebersold R, Sonenberg N. Hierarchical phosphorylation of the translation inhibitor 4E-BP1. Genes Dev 2001, 15:2852-2864. 312813, 11691836.
15. Kerekatte V, Smiley K, Hu B, Smith A, Gelder F, De Benedetti A. The proto-oncogene/translation factor eIF4E: a survey of its expression in breast carcinomas. Int J Cancer 1995, 64:27-31. 10.1002/ijc.2910640107, 7665244.
16. Fredersdorf S, Burns J, Milne AM, Packham G, Fallis L, Gillett CE, Royds JA, Peston D, Hall PA, Hanby AM, et al. High level expression of p27(kip1) and cyclin D1 in some human breast cancer cells: inverse correlation between the expression of p27(kip1) and degree of malignancy in human breast and colorectal cancers. Proc Natl Acad Sci USA 1997, 94:6380-6385. 10.1073/pnas.94.12.6380, 21058, 9177226.
17. Weinstat-Saslow D, Merino MJ, Manrow RE, Lawrence JA, Bluth RF, Wittenbel KD, Simpson JF, Page DL, Steeg PS. Overexpression of cyclin D mRNA distinguishes invasive and in situ breast carcinomas from non-malignant lesions. Nat Med 1995, 1:1257-1260. 10.1038/nm1295-1257, 7489405.
18. Liao DJ, Dickson RB. c-Myc in breast cancer. Endocr Relat Cancer 2000, 7:143-164. 10.1677/erc.0.0070143, 11021963.
19. Baselga J. Targeting the phosphoinositide-3 (PI3) kinase pathway in breast cancer. Oncologist 2011, 16(Suppl 1):12-19.
20. Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol 2009, 27:2278-2287. 10.1200/JCO.2008.20.0766, 2738634, 19332717.
21. Dowling RJ, Topisirovic I, Alain T, Bidinosti M, Fonseca BD, Petroulakis E, Wang X, Larsson O, Selvaraj A, Liu Y, et al. mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs. Science 2010, 328:1172-1176. 10.1126/science.1187532, 2893390, 20508131.
22. Baselga J, Fumoleau P, Gil M, Colomer R, Roche H, Cortes-Funes H, Burstein H, Kaufman P, Kong S, Moore L. Phase II 3-arm study of CCI-779 in combination with letrozole in postmenopausal women with locally advanced or metastatic breast cancer: preliminary results. Proc Am Soc Clin Oncol 2004, 23:A544.
23. Baselga J, Semiglazov V, van Dam P, Manikhas A, Bellet M, Mayordomo J, Campone M, Kubista E, Greil R, Bianchi G, Steinseifer J, Molloy B, Tokaji E, Gardner H, Phillips P, Stumm M, Lane HA, Dixon JM, Jonat W, Rugo HS. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol 2009, 27:2630-2637. 10.1200/JCO.2008.18.8391, 19380449.
24. Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, Abadie-Lacourtoisie S, Eymard JC, Debled M, Spaëth D, Legouffe E, Allouache D, El Kouri C, Pujade-Lauraine E. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol 2012, 30:2718-2724. 10.1200/JCO.2011.39.0708, 22565002.
25. Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012, 366:520-529. 10.1056/NEJMoa1109653, 22149876.
26. Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M, Botero ML, Llonch E, Atzori F, Di Cosimo S, Maira M, Garcia-Echeverria C, Parra JL, Arribas J, Baselga J. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res 2008, 68:8022-8030. 10.1158/0008-5472.CAN-08-1385, 18829560.
27. Banerjee S, Zvelebil M, Furet P, Mueller-Vieira U, Evans DB, Dowsett M, Martin LA. The vascular endothelial growth factor receptor inhibitor PTK787/ZK222584 inhibits aromatase. Cancer Res 2009, 69:4716-4723. 10.1158/0008-5472.CAN-08-4711, 19435899.
28. Evans AH, Pancholi S, Farmer I, Thornhill A, Evans DB, Johnston SR, Dowsett M, Martin LA. EGFR/HER2 inhibitor AEE788 increases ER-mediated transcription in HER2/ER-positive breast cancer cells but functions synergistically with endocrine therapy. Br J Cancer 2010, 102:1235-1243. 10.1038/sj.bjc.6605641, 2856013, 20386540.
29. Darbre PD, Curtis S, King RJ. Effects of estradiol and tamoxifen on human breast cancer cells in serum-free culture. Cancer Res 1984, 44:2790-2793.
30. Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 1984, 22:27-55.
31. Martin LA, Farmer I, Johnston SR, Ali S, Marshall C, Dowsett M. Enhanced estrogen receptor (ER) alpha, ERBB2, and MAPK signal transduction pathways operate during the adaptation of MCF-7 cells to long term estrogen deprivation. J Biol Chem 2003, 278:30458-30468. 10.1074/jbc.M305226200, 12775708.
32. Martin LA, Head JE, Pancholi S, Salter J, Quinn E, Detre S, Kaye S, Howes A, Dowsett M, Johnston SR. The farnesyltransferase inhibitor R115777 (tipifarnib) in combination with tamoxifen acts synergistically to inhibit MCF-7 breast cancer cell proliferation and cell cycle progression in vitro and in vivo. Mol Cancer Ther 2007, 6:2458-2467. 10.1158/1535-7163.MCT-06-0452, 17876043.
33. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, Lane H, Hofmann F, Hicklin DJ, Ludwig DL, Baselga J, Rosen N. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006, 66:1500-1508. 10.1158/0008-5472.CAN-05-2925, 3193604, 16452206.
34. Liang J, Zubovitz J, Petrocelli T, Kotchetkov R, Connor MK, Han K, Lee JH, Ciarallo S, Catzavelos C, Beniston R, Franssen E, Slingerland JM. PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med 2002, 8:1153-1160. 10.1038/nm761, 12244302.
35. Yamnik RL, Digilova A, Davis DC, Brodt ZN, Murphy CJ, Holz MK. S6 kinase 1 regulates estrogen receptor alpha in control of breast cancer cell proliferation. J Biol Chem 2009, 284:6361-6369.
36. Arpino G, Wiechmann L, Osborne CK, Schiff R. Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: molecular mechanism and clinical implications for endocrine therapy resistance. Endocr Rev 2008, 29:217-233. 2528847, 18216219.
37. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 2009, 9:550-562. 10.1038/nrc2664, 19629070.
38. Yu K, Toral-Barza L, Discafani C, Zhang WG, Skotnicki J, Frost P, Gibbons JJ. mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer 2001, 8:249-258. 10.1677/erc.0.0080249, 11566616.
39. Gera JF, Mellinghoff IK, Shi Y, Rettig MB, Tran C, Hsu JH, Sawyers CL, Lichtenstein AK. AKT activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-myc expression. J Biol Chem 2004, 279:2737-2746.
40. Boulay A, Rudloff J, Ye J, Zumstein-Mecker S, O'Reilly T, Evans DB, Chen S, Lane HA. Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. Clin Cancer Res 2005, 11:5319-5328. 10.1158/1078-0432.CCR-04-2402, 16033851.
41. Chang SB, Miron P, Miron A, Iglehart JD. Rapamycin inhibits proliferation of estrogen-receptor-positive breast cancer cells. J Surg Res 2007, 138:37-44. 10.1016/j.jss.2006.07.003, 17109887.
42. Ghayad SE, Bieche I, Vendrell JA, Keime C, Lidereau R, Dumontet C, Cohen PA. mTOR inhibition reverses acquired endocrine therapy resistance of breast cancer cells at the cell proliferation and gene-expression levels. Cancer Sci 2008, 99:1992-2003.
43. deGraffenried LA, Friedrichs WE, Russell DH, Donzis EJ, Middleton AK, Silva JM, Roth RA, Hidalgo M. Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity. Clin Cancer Res 2004, 10:8059-8067. 10.1158/1078-0432.CCR-04-0035, 15585641.
44. Becker MA, Ibrahim YH, Cui X, Lee AV, Yee D. The IGF pathway regulates ERalpha through a S6K1-dependent mechanism in breast cancer cells. Mol Endocrinol 2011, 25:516-528. 10.1210/me.2010-0373, 3045742, 21292829.
45. Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, Egia A, Sasaki AT, Thomas G, Kozma SC, Papa A, Nardella C, Cantley LC, Baselga J, Pandolfi PP. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 2008, 118:3065-3074. 2518073, 18725988.
46. Tabernero J, Rojo F, Calvo E, Burris H, Judson I, Hazell K, Martinelli E, Ramon Y, Cajal S, Jones S, Vidal L, Shand N, Macarulla T, Ramos FJ, Dimitrijevic S, Zoellner U, Tang P, Stumm M, Lane HA, Lebwohl D, Baselga J. Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 2008, 26:1603-1610. 10.1200/JCO.2007.14.5482, 18332469.
47. Xia W, Bisi J, Strum J, Liu L, Carrick K, Graham KM, Treece AL, Hardwicke MA, Dush M, Liao Q, Westlund RE, Zhao S, Bacus S, Spector NL. Regulation of survivin by ErbB2 signaling: therapeutic implications for ErbB2-overexpressing breast cancers. Cancer Res 2006, 66:1640-1647. 10.1158/0008-5472.CAN-05-2000, 16452223.
48. Wang S, Huang X, Lee CK, Liu B. Elevated expression of erbB3 confers paclitaxel resistance in erbB2-overexpressing breast cancer cells via upregulation of Survivin. Oncogene 2010, 29:4225-4236. 10.1038/onc.2010.180, 20498641.