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

121 Citations (Scopus)

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

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Gastrointestinal Stromal Tumors
Autophagy
Antimalarials
Cell Death
Platelet-Derived Growth Factor Receptors
Stromal Cells
RNA Interference
Treatment Failure
Mutation
Survival
Therapeutics
Imatinib Mesylate
Neoplasms

Keywords

  • Imatinib
  • Quiescence
  • Targeted therapy

ASJC Scopus subject areas

  • General

Cite this

Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST). / Gupta, Anu; Roy, Srirupa; Lazar, Alexander J.F.; Wang, Wei Lien; McAuliffe, John C.; Reynoso, David; McMahon, James; Taguchi, Takahiro; Floris, Giuseppe; Debiec-Rychter, Maria; Schoffski, Patrick; Trent, Jonathan A.; Debnath, Jayanta; Rubin, Brian P.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 32, 10.08.2010, p. 14333-14338.

Research output: Contribution to journalArticle

Gupta, A, Roy, S, Lazar, AJF, Wang, WL, McAuliffe, JC, Reynoso, D, McMahon, J, Taguchi, T, Floris, G, Debiec-Rychter, M, Schoffski, P, Trent, JA, Debnath, J & Rubin, BP 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, vol. 107, no. 32, pp. 14333-14338. https://doi.org/10.1073/pnas.1000248107
Gupta, Anu ; Roy, Srirupa ; Lazar, Alexander J.F. ; Wang, Wei Lien ; McAuliffe, John C. ; Reynoso, David ; McMahon, James ; Taguchi, Takahiro ; Floris, Giuseppe ; Debiec-Rychter, Maria ; Schoffski, Patrick ; Trent, Jonathan A. ; Debnath, Jayanta ; Rubin, Brian P. / Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST). In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 32. pp. 14333-14338.
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