MTOR inhibition enhances NVP-AUY922-induced autophagy-mediated KIT degradation and cytotoxicity in imatinib-resistant gastrointestinal stromal tumors
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Yuan-Shuo Hsueh1, Hui Hua Chang2, Nai-Jung Chiang1,3, Chueh-Chuan Yen4,5, Chien-Feng Li1,6,7,8 and Li-Tzong Chen1,2,3,9
1 National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
2 Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
3 Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
4 Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
5 National Yang-Ming University School of Medicine, Taipei, Taiwan
6 Department of Pathology, Chi-Mei Foundation Medical Center, Tainan, Taiwan
7 Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan
8 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
9 Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwann
Li-Tzong Chen, email:
Chien-Feng Li, email:
Keywords: gastrointestinal stromal tumor, KIT, heat shock protein 90 inhibitor, MTOR inhibitor, autophagy
Received: June 19, 2014 Accepted: October 21, 2014 Published: October 21, 2014
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.
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