Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST).
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.
Gupta
Anu
A
Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Roy
Srirupa
S
Lazar
Alexander J F
AJ
Wang
Wei-Lien
WL
McAuliffe
John C
JC
Reynoso
David
D
McMahon
James
J
Taguchi
Takahiro
T
Floris
Giuseppe
G
Debiec-Rychter
Maria
M
Schoffski
Patrick
P
Trent
Jonathan A
JA
Debnath
Jayanta
J
Rubin
Brian P
BP
D000962:Antimalarials / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D001549:Benzamides; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004359:Drug Therapy, Combination; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology
D000962:Antimalarials; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate