MTOR inhibition enhances NVP-AUY922-induced autophagymediated KIT degradation and cytotoxicity in imatinib-resistant gastrointestinal stromal tumors

Yuan Shuo Hsueh, Hui Hua Chang, Nai Jung Chiang, Chueh Chuan Yen, Chien Feng Li, Li Tzong Chen

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)11711-11724
Number of pages14
JournalOncotarget
Volume5
Issue number22
DOIs
Publication statusPublished - 2014

All Science Journal Classification (ASJC) codes

  • Oncology

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