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

Anu Gupta, Srirupa Roy, Alexander J F Lazar, Wei Lien Wang, John C. McAuliffe, David Reynoso, James McMahon, Takahiro Taguchi, Giuseppe Floris, Maria Debiec-Rychter, Patrick Schoffski, Jonathan Trent, Jayanta Debnath, Brian P. Rubin

Research output: Contribution to journalArticle

125 Scopus citations

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.

Original languageEnglish
Pages (from-to)14333-14338
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number32
DOIs
StatePublished - Aug 10 2010
Externally publishedYes

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Keywords

  • Imatinib
  • Quiescence
  • Targeted therapy

ASJC Scopus subject areas

  • General

Cite this

Gupta, A., Roy, S., Lazar, A. J. F., Wang, W. L., McAuliffe, J. C., Reynoso, D., McMahon, J., Taguchi, T., Floris, G., Debiec-Rychter, M., Schoffski, P., Trent, J., Debnath, J., & Rubin, B. P. (2010). Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST). Proceedings of the National Academy of Sciences of the United States of America, 107(32), 14333-14338. https://doi.org/10.1073/pnas.1000248107