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

A Gupta, S Roy, AJF Lazar, WL Wang… - Proceedings of the …, 2010 - National Acad Sciences
A Gupta, S Roy, AJF Lazar, WL Wang, JC McAuliffe, D Reynoso, J McMahon, T Taguchi
Proceedings of the National Academy of Sciences, 2010National Acad Sciences
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 …
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.
National Acad Sciences