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 A. Trent, Jayanta Debnath, Brian P. Rubin

Research output: Contribution to journalArticle

133 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 (US)
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

Keywords

  • Imatinib
  • Quiescence
  • Targeted therapy

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST)'. Together they form a unique fingerprint.

  • 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. A., 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