MTOR inhibition enhances NVP-AUY922-induced autophagy-mediated KIT degradation and cytotoxicity in imatinib-resistant gastrointestinal stromal tumors.
Our previous study demonstrated NVP-AUY922, a HSP90AA1 inhibitor, could enhance mutant KIT degradation in gastrointestinal stromal tumor (GIST) cells through both proteasome- and autophagy-mediated pathways. Herein, we showed rapamycin, a MTOR inhibitor and autophagy inducer, could reduce total and phospho-KIT expression levels and enhance apoptosis in imatinib-resistant GIST cells. The involvement of autophagy in rapamycin-induced KIT downregulation was further confirmed by co-localization of KIT and autophagosome, and partial recovery of KIT expression level by either siRNA-mediated BECN1 and ATG5 silencing or autophagy inhibitors after rapamycin. Rapamycin and NVP-AUY922 synergistically inhibited GIST cells growth in vitro. The combination of low-dose NVP-AUY922 with rapamycin had comparable effects on reducing KIT expression, increasing MAP1LC3B puncta and tumor necrosis, and inhibiting tumor growth as high-dose NVP-AUY922 did in GIST430 xenograft model. Our results suggest the addition of a MTOR inhibitor may reduce NVP-AUY922 dose requirement and potentially improve its therapeutic index in mutant KIT-expressing GISTs.
National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
Yuan-Shuo
YS
Hsueh
Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Hui Hua
HH
Chang
National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan. Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
Nai-Jung
NJ
Chiang
Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. National Yang-Ming University School of Medicine, Taipei, Taiwan.
Chueh-Chuan
CC
Yen
National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan. Department of Pathology, Chi-Mei Foundation Medical Center, Tainan, Taiwan. Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Chien-Feng
CF
Li
National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan. Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan. Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwann.
Li-Tzong
LT
Chen
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D017209:Apoptosis; D001343:Autophagy; D001549:Benzamides / Q000737:chemistry; D016923:Cell Death; D002470:Cell Survival; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000737:chemistry; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D009336:Necrosis; D009368:Neoplasm Transplantation; D010879:Piperazines / Q000737:chemistry; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011743:Pyrimidines / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012118:Resorcinols / Q000737:chemistry; D020123:Sirolimus / Q000737:chemistry; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D001549:Benzamides; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D010879:Piperazines; D011743:Pyrimidines; D034741:RNA, Small Interfering; D012118:Resorcinols; D000068877:Imatinib Mesylate; C546842:MTOR protein, human; D019009:Proto-Oncogene Proteins c-kit; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus