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Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14333-8. doi: 10.1073/pnas.1000248107. Epub 2010 Jul 26.

Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST).

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  • 1Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Abstract

Although gastrointestinal stromal tumors (GISTs) harboring activating KIT or platelet-derived growth factor receptor A (PDGFRA) mutations respond to treatment with targeted KIT/PDGFRA inhibitors such as imatinib mesylate, these treatments are rarely curative. Most often, a sizeable tumor cell subpopulation survives and remains quiescent for years, eventually resulting in acquired resistance and treatment failure. Here, we report that imatinib induces autophagy as a survival pathway in quiescent GIST cells. Inhibiting autophagy, using RNAi-mediated silencing of autophagy regulators (ATGs) or antimalarial lysosomotrophic agents, promotes the death of GIST cells both in vitro and in vivo. Thus, combining imatinib with autophagy inhibition represents a potentially valuable strategy to promote GIST cytotoxicity and to diminish both cellular quiescence and acquired resistance in GIST patients.

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PMID:
20660757
[PubMed - indexed for MEDLINE]
PMCID:
PMC2922542
Free PMC Article
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