Oncotarget

Research Papers:

MTOR inhibition enhances NVP-AUY922-induced autophagy-mediated 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 and Li-Tzong Chen _

PDF  |  HTML  |  How to cite  |  Order a Reprint

Oncotarget. 2014; 5:11723-11736. https://doi.org/10.18632/oncotarget.2607

Metrics: PDF 1434 views  |   HTML 1283 views  |   ?  


Abstract

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

Correspondence:

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

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 2607