title: Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST).
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.
authors.affiliation: Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Anu
authors.initials: A
authors.lastname: Gupta
authors.forename: Srirupa
authors.initials: S
authors.lastname: Roy
authors.forename: Alexander J F
authors.initials: AJ
authors.lastname: Lazar
authors.forename: Wei-Lien
authors.initials: WL
authors.lastname: Wang
authors.forename: John C
authors.initials: JC
authors.lastname: McAuliffe
authors.forename: David
authors.initials: D
authors.lastname: Reynoso
authors.forename: James
authors.initials: J
authors.lastname: McMahon
authors.forename: Takahiro
authors.initials: T
authors.lastname: Taguchi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Floris
authors.forename: Maria
authors.initials: M
authors.lastname: Debiec-Rychter
authors.forename: Patrick
authors.initials: P
authors.lastname: Schoffski
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Trent
authors.forename: Jayanta
authors.initials: J
authors.lastname: Debnath
authors.forename: Brian P
authors.initials: BP
authors.lastname: Rubin
mesh_terms: 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
chemical_list: D000962:Antimalarials; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate