PI3K-independent mTOR activation promotes lapatinib resistance and IAP expression that can be effectively reversed by mTOR and Hsp90 inhibition

References

• Slamon D, Godolphin W, Jones L, Holt J, Wong S, Keith D, Levin W, Stuart S, Udove J, Ullrich A, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989; 244:707-12; PMID:2470152; http://dx.doi.org/10.1126/science.2470152.
   PubMed Web of Science ®Google Scholar
• Esteva FJ, Yu D, Hung M-C, Hortobagyi GN. Molecular predictors of response to trastuzumab and lapatinib in breast cancer. Nat Rev Clin Oncol 2010; 7:98-107; PMID:20027191; http://dx.doi.org/10.1038/nrclinonc.2009.216.
   PubMed Web of Science ®Google Scholar
• Garrett JT, Arteaga CL. Resistance to HER2-directed antibodies and tyrosine kinase inhibitors: Mechanisms and clinical implications. Cancer Biol Ther 2011; 11:793-800; PMID:21307659; http://dx.doi.org/10.4161/cbt.11.9.15045.
   PubMed Web of Science ®Google Scholar
• Arteaga CL, Sliwkowski MX, Osborne CK, Perez EA, Puglisi F, Gianni L. Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol 2012; 9:16-32; http://dx.doi.org/10.1038/nrclinonc.2011.177.
   PubMed Web of Science ®Google Scholar
• Wang Q, Li S-H, Wang H, Xiao Y, Sahin O, Brady SW, Li P, Ge H, Jaffee EM, Muller WJ, et al. Concomitant targeting of tumor cells and induction of T-cell response synergizes to effectively inhibit trastuzumab-resistant breast cancer. Cancer Res 2012; 72:4417-28; PMID:22773664; http://dx.doi.org/10.1158/0008-5472.CAN-12-1339-T.
   PubMed Web of Science ®Google Scholar
• Zhang S, Huang W-C, Li P, Guo H, Poh S-B, Brady SW, Xiong Y, Tseng L-M, Li S-H, Ding Z, et al. Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat Med 2011; 17:461-9; PMID:21399647; http://dx.doi.org/10.1038/nm.2309.
   PubMed Web of Science ®Google Scholar
• Nagata Y, Lan K-H, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004; 6:117-27; PMID:15324695; http://dx.doi.org/10.1016/j.ccr.2004.06.022.
   PubMed Web of Science ®Google Scholar
• Sahin O, Wang Q, Brady SW, Ellis K, Wang H, Chang C-C, Zhang Q, Priya P, Zhu R, Wong ST, et al. Biomarker-guided sequential targeted therapies to overcome therapy resistance in rapidly evolving highly aggressive mammary tumors. Cell Res 2014; 24:542-59; PMID:24675532; http://dx.doi.org/10.1038/cr.2014.37.
   PubMed Web of Science ®Google Scholar
• Lu C-H, Wyszomierski SL, Tseng L-M, Sun M-H, Lan K-H, Neal CL, Mills GB, Hortobagyi GN, Esteva FJ, Yu D. Preclinical testing of clinically applicable strategies for overcoming trastuzumab resistance caused by PTEN deficiency. Clin Cancer Res 2007; 13:5883-8; PMID:17908983; http://dx.doi.org/10.1158/1078-0432.CCR-06-2837.
   PubMed Web of Science ®Google Scholar
• Wang L, Zhang Q, Zhang J, Sun S, Guo H, Jia Z, Wang B, Shao Z, Wang Z, Hu X. PI3K pathway activation results in low efficacy of both trastuzumab and lapatinib. BMC Cancer 2011; 11:248; PMID:21676217; http://dx.doi.org/10.1186/1471-2407-11-248.
   PubMed Web of Science ®Google Scholar
• Eichhorn PJA, Gili M, Scaltriti M, Serra V, Guzman M, Nijkamp W, Beijersbergen RL, Valero V, Seoane J, Bernards R, et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 2008; 68:9221-30; PMID:19010894; http://dx.doi.org/10.1158/0008-5472.CAN-08-1740.
   PubMed Web of Science ®Google Scholar
• Liu L, Greger J, Shi H, Liu Y, Greshock J, Annan R, Halsey W, Sathe GM, Martin A-M, Gilmer TM. Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL. Cancer Res 2009; 69:6871-8; PMID:19671800; http://dx.doi.org/10.1158/0008-5472.CAN-08-4490.
   PubMed Web of Science ®Google Scholar
• Jegg A-M, Ward TM, Iorns E, Hoe N, Zhou J, Liu X, Singh S, Landgraf R, Pegram MD. PI3K independent activation of mTORC1 as a target in lapatinib-resistant ERBB2+ breast cancer cells. Breast Cancer Res Treat 2012; 136:683-92; PMID:23089982; http://dx.doi.org/10.1007/s10549-012-2252-9.
   PubMed Web of Science ®Google Scholar
• Fingar DC, Richardson CJ, Tee AR, Cheatham L, Tsou C, Blenis J. mTOR Controls Cell Cycle Progression through Its Cell Growth Effectors S6K1 and 4E-BP1/Eukaryotic Translation Initiation Factor 4E. Mol Cell Biol 2003; 24:200-16; http://dx.doi.org/10.1128/MCB.24.1.200-216.2004.
   Web of Science ®Google Scholar
• Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012; 149:274-93; PMID:22500797; http://dx.doi.org/10.1016/j.cell.2012.03.017.
   PubMed Web of Science ®Google Scholar
• Inoki K, Li Y, Xu T, Guan K-L. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 2003; 17:1829-34; PMID:12869586; http://dx.doi.org/10.1101/gad.1110003.
   PubMed Web of Science ®Google Scholar
• Qi J, McTigue MA, Rogers A, Lifshits E, Christensen JG, Jänne PA, Engelman JA. Multiple mutations and bypass mechanisms can contribute to development of acquired resistance to MET inhibitors. Cancer Res 2011; 71:1081-91; PMID:21266357; http://dx.doi.org/10.1158/0008-5472.CAN-10-1623.
   PubMed Web of Science ®Google Scholar
• Burrell RA, Swanton C. Tumour heterogeneity and the evolution of polyclonal drug resistance. Mol Oncol 2014; 8:1095-1111; PMID:25087573; http://dx.doi.org/10.1016/j.molonc.2014.06.005.
   PubMed Web of Science ®Google Scholar
• Maira S-M, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, Brachmann S, Chène P, De Pover A, Schoemaker K, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther 2008; 7:1851-63; PMID:18606717; http://dx.doi.org/10.1158/1535-7163.MCT-08-0017.
   PubMed Web of Science ®Google Scholar
• Folkes AJ, Ahmadi K, Alderton WK, Alix S, Baker SJ, Box G, Chuckowree IS, Clarke PA, Depledge P, Eccles SA, et al. The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer . J Med Chem 2008; 51:5522-32; PMID:18754654; http://dx.doi.org/10.1021/jm800295d.
   PubMed Web of Science ®Google Scholar
• Hirai H, Sootome H, Nakatsuru Y, Miyama K, Taguchi S, Tsujioka K, Ueno Y, Hatch H, Majumder PK, Pan B-S, et al. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther 2010; 9:1956-67; PMID:20571069; http://dx.doi.org/10.1158/1535-7163.MCT-09-1012.
   PubMed Web of Science ®Google Scholar
• Futreal PA, Coin L, Marshall M, Down T, Hubbard T, Wooster R, Rahman N, Stratton MR. A census of human cancer genes. Nat Rev Cancer 2004; 4:177-83; PMID:14993899; http://dx.doi.org/10.1038/nrc1299.
   PubMed Web of Science ®Google Scholar
• Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM, Manola J, Brugarolas J, McDonnell TJ, Golub TR, et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 2004; 10:594-601; PMID:15156201; http://dx.doi.org/10.1038/nm1052.
   PubMed Web of Science ®Google Scholar
• Tait SWG, Green DR. Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 2010; 11:621-32; PMID:20683470; http://dx.doi.org/10.1038/nrm2952.
   PubMed Web of Science ®Google Scholar
• Wang J-M, Chao J-R, Chen W, Kuo M-L, Yen JJ-Y, Yang-Yen H-F. The antiapoptotic gene mcl-1 is up-regulated by the phosphatidylinositol 3-kinase/Akt signaling pathway through a transcription factor complex containing CREB. Mol Cell Biol 1999; 19:6195-206; PMID:10454566.
   PubMed Web of Science ®Google Scholar
• Takezawa K, Okamoto I, Nishio K, Jänne PA, Nakagawa K. Role of ERK-BIM and STAT3-survivin signaling pathways in ALK inhibitor-induced apoptosis in EML4-ALK-positive lung cancer. Clin Cancer Res 2011; 17:2140-8; PMID:21415216; http://dx.doi.org/10.1158/1078-0432.CCR-10-2798.
   PubMed Web of Science ®Google Scholar
• Datta S. Akt Phosphorylation of BAD Couples Survival Signals to the Cell-Intrinsic Death Machinery. Cell 1997; 91:231-41; PMID:9346240; http://dx.doi.org/10.1016/S0092-8674(00)80405-5.
   PubMed Web of Science ®Google Scholar
• Czabotar PE, Lessene G, Strasser A, Adams JM. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 2014; 15:49-63; PMID:24355989; http://dx.doi.org/10.1038/nrm3722.
   PubMed Web of Science ®Google Scholar
• Tamm I, Wang Y, Sausville E, Scudiero DA, Vigna N, Oltersdorf T, Reed JC. IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. Cancer Res 1998; 58:5315-20; PMID:9850056.
   PubMed Web of Science ®Google Scholar
• Hunter AM, LaCasseEC, Korneluk RG. The inhibitors of apoptosis (IAPs) as cancer targets. Apoptosis 2007; 12:1543-68; PMID:17573556; http://dx.doi.org/10.1007/s10495-007-0087-3.
   PubMed Web of Science ®Google Scholar
• Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, Alnemri ES, Salvesen GS, Reed JC. IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J 1998; 17:2215-23; PMID:9545235; http://dx.doi.org/10.1093/emboj/17.8.2215.
   PubMed Web of Science ®Google Scholar
• The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012; 490:61-70; PMID:23000897; http://dx.doi.org/10.1038/nature11412.
   PubMed Web of Science ®Google Scholar
• Benetatos CA, Mitsuuchi Y, Burns JM, Neiman EM, Condon SM, Yu G, Seipel ME, Kapoor GS, Laporte MG, Rippin SR, et al. Birinapant (TL32711), a bivalent SMAC mimetic, targets TRAF2-associated cIAPs, abrogates TNF-induced NF-κB activation, and is active in patient-derived xenograft models. Mol Cancer Ther 2014; 13:867-79; PMID:24563541; http://dx.doi.org/10.1158/1535-7163.MCT-13-0798.
   PubMed Web of Science ®Google Scholar
• Krepler C, Chunduru SK, Halloran MB, He X, Xiao M, Vultur A, Villanueva J, Mitsuuchi Y, Neiman EM, Benetatos C, et al. The novel SMAC mimetic birinapant exhibits potent activity against human melanoma cells. Clin Cancer Res 2013; 19:1784-94; PMID:23403634; http://dx.doi.org/10.1158/1078-0432.CCR-12-2518.
   PubMed Web of Science ®Google Scholar
• Allensworth JL, Sauer SJ, Lyerly HK, Morse MA, Devi GR. Smac mimetic Birinapant induces apoptosis and enhances TRAIL potency in inflammatory breast cancer cells in an IAP-dependent and TNF-α-independent mechanism. Breast Cancer Res Treat 2013; 137:359-71; PMID:23225169; http://dx.doi.org/10.1007/s10549-012-2352-6.
   PubMed Web of Science ®Google Scholar
• Fortugno P, Beltrami E, Plescia J, Fontana J, Pradhan D, Marchisio PC, Sessa WC, Altieri DC. Regulation of survivin function by Hsp90. Proc Natl Acad Sci U S A 2003; 100:13791-6; PMID:14614132; http://dx.doi.org/10.1073/pnas.2434345100.
   PubMed Web of Science ®Google Scholar
• Trepel J, Mollapour M, Giaccone G, Neckers L. Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer 2010; 10:537-49; PMID:20651736; http://dx.doi.org/10.1038/nrc2887.
   PubMed Web of Science ®Google Scholar
• Solit DB, Zheng FF, Drobnjak M, Munster PN, Higgins B, Verbel D, Heller G, Tong W, Cordon-Cardo C, Agus DB, et al. Seventeen-allylamino-17-demethoxygeldanamycin induces the degradation of androgen receptor and HER-2/neu and inhibits the growth of prostate cancer xenografts. Clin Cancer Res 2002; 8:986-93; PMID:12006510.
   PubMed Web of Science ®Google Scholar
• Modi S, Stopeck AT, Gordon MS, Mendelson D, Solit DB, Bagatell R, Ma W, Wheler J, Rosen N, Norton L, et al. Combination of trastuzumab and tanespimycin (17-AAG, KOS-953) is safe and active in trastuzumab-refractory HER-2 overexpressing breast cancer: a phase I dose-escalation study. J Clin Oncol 2007; 25:5410-7; PMID:18048823; http://dx.doi.org/10.1200/JCO.2007.11.7960.
   PubMed Web of Science ®Google Scholar
• Modi S, Stopeck A, Linden H, Solit D, Chandarlapaty S, Rosen N, D'Andrea G, Dickler M, Moynahan ME, Sugarman S, et al. HSP90 inhibition is effective in breast cancer: a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab. Clin Cancer Res 2011; 17:5132-9; PMID:21558407; http://dx.doi.org/10.1158/1078-0432.CCR-11-0072.
   PubMed Web of Science ®Google Scholar
• Li F, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio PC, Altieri DC. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 1998; 396:580-4; PMID:9859993; http://dx.doi.org/10.1038/25141.
   PubMed Web of Science ®Google Scholar
• Dubrez-Daloz L, Dupoux A, Cartier J. More than just inhibitors of apoptosis proteins. Cell Cycle 2008; 7:1036-1046; PMID:18414036; http://dx.doi.org/10.4161/cc.7.8.5783.
   PubMed Web of Science ®Google Scholar
• Nimmanapalli R, O'Bryan E, Kuhn D, Yamaguchi H, Wang H-G, Bhalla KN. Regulation of 17-AAG-induced apoptosis: role of Bcl-2, Bcl-XL, and Bax downstream of 17-AAG-mediated down-regulation of Akt, Raf-1, and Src kinases. Blood 2003; 102:269-75; PMID:12623837; http://dx.doi.org/10.1182/blood-2002-12-3718.
   PubMed Web of Science ®Google Scholar
• Fumo G, Akin C, Metcalfe DD, Neckers L. . 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is effective in down-regulating mutated, constitutively activated KIT protein in human mast cells. Blood 2004; 103:1078-84; PMID:14551138; http://dx.doi.org/10.1182/blood-2003-07-2477.
   PubMed Web of Science ®Google Scholar
• Georgakis G V, Li Y, Younes A. The heat shock protein 90 inhibitor 17-AAG induces cell cycle arrest and apoptosis in mantle cell lymphoma cell lines by depleting cyclin D1, Akt, Bid and activating caspase 9. Br J Haematol 2006; 135:68-71; PMID:16925576; http://dx.doi.org/10.1111/j.1365-2141.2006.06247.x.
   PubMed Web of Science ®Google Scholar
• Radujkovic A, Schad M, Topaly J, Veldwijk MR, Laufs S, Schultheis BS, Jauch A, Melo J V, Fruehauf S, Zeller WJ. Synergistic activity of imatinib and 17-AAG in imatinib-resistant CML cells overexpressing BCR-ABL-Inhibition of P-glycoprotein function by 17-AAG. Leukemia 2005; 19:1198-206; PMID:15902298; http://dx.doi.org/10.1038/sj.leu.2403764.
   PubMed Web of Science ®Google Scholar
• Smith-Jones PM, Solit DB, Akhurst T, Afroze F, Rosen N, Larson SM. Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors. Nat Biotechnol 2004; 22:701-6; PMID:15133471; http://dx.doi.org/10.1038/nbt968.
   PubMed Web of Science ®Google Scholar
• Johnston S, Pippen J, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ, et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol 2009; 27:5538-46; PMID:19786658; http://dx.doi.org/10.1200/JCO.2009.23.3734.
   PubMed Web of Science ®Google Scholar
• Asahina H, Nokihara H, Yamamoto N, Yamada Y, Tamura Y, Honda K, Seki Y, Tanabe Y, Shimada H, Shi X, et al. Safety and tolerability of AZD8055 in Japanese patients with advanced solid tumors; a dose-finding phase I study. Invest New Drugs 2013; 31:677-84; PMID:22843211; http://dx.doi.org/10.1007/s10637-012-9860-4.
   PubMed Web of Science ®Google Scholar
• Pallet N, Legendre C. Adverse events associated with mTOR inhibitors. Expert Opin Drug Saf 2013; 12:177-86; PMID:23252795; http://dx.doi.org/10.1517/14740338.2013.752814.
   PubMed Web of Science ®Google Scholar
• Neckers L, Workman P. Hsp90 molecular chaperone inhibitors: are we there yet? Clin Cancer Res 2012; 18:64-76; PMID:22215907; http://dx.doi.org/10.1158/1078-0432.CCR-11-1000.
   PubMed Web of Science ®Google Scholar
• Banerji U, O'Donnell A, Scurr M, Pacey S, Stapleton S, Asad Y, Simmons L, Maloney A, Raynaud F, Campbell M, et al. Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. J Clin Oncol 2005; 23:4152-61; PMID:15961763; http://dx.doi.org/10.1200/JCO.2005.00.612.
   PubMed Web of Science ®Google Scholar