Article

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

Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 08/2010; 107(32):14333-8. DOI: 10.1073/pnas.1000248107
Source: PubMed

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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Available from: Maria Debiec-Rychter, Jul 30, 2015
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    • "Quinacrine, which also has been used in patients as an anti-malarial in the past, has been shown to inhibit autophagy similarly to CQ. In fact, quinacrine showed greater cytotoxicity in gastrointestinal stromal tumor (GIST) cell lines treated with imatinib than CQ (Gupta et al. 2010), and therefore this may be a promising anti-autophagy agent for future clinical trials. Given the complexity of the autophagic process, there are multiple additional points that are potential targets for therapeutic intervention. "
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    • "Upon inhibiting autophagy using RNAi-mediated ATG depletion or antimalarials such as quinacrine, GIST cells undergo high levels of apoptosis both in vitro and in vivo. Thus, autophagy appears critical for the establishment of a dormant state in which GIST cells can survive indefinitely (Gupta et al., 2010). Moreover, these results in GIST broach the exciting idea that autophagy can be more widely exploited to kill or prevent the expansion of quiescent or dormant cancer cells, which are notorious for their resistance to both conventional and targeted therapies (Rubin and Debnath, 2010). "
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