title: Opposing roles of KIT and ABL1 in the therapeutic response of gastrointestinal stromal tumor (GIST) cells to imatinib mesylate.
abstract: Most gastrointestinal stromal tumors (GISTs) are caused by activating mutations of the KIT receptor tyrosine kinase. The small molecule inhibitor imatinib mesylate was initially developed to target the ABL1 kinase, which is constitutively activated through chromosomal translocation in BCR-ABL1-positive chronic myeloid leukemia. Because of cross-reactivity of imatinib against the KIT kinase, the drug is also successfully used for the treatment of GIST. Although inhibition of KIT clearly has a major role in the therapeutic response of GIST to imatinib, the contribution of concomitant inhibition of ABL in this context has never been explored. We show here that ABL1 is expressed in the majority of GISTs, including human GIST cell lines. Using siRNA-mediated knockdown, we demonstrate that depletion of KIT in conjunction with ABL1 - hence mimicking imatinib treatment - leads to reduced apoptosis induction and attenuated inhibition of cellular proliferation when compared to depletion of KIT alone. These results are explained by an increased activity of the AKT survival kinase, which is mediated by the cyclin-dependent kinase CDK2, likely through direct phosphorylation. Our results highlight that distinct inhibitory properties of targeted agents can impede antitumor effects and hence provide insights for rational drug development. Novel KIT-targeted agents to treat GIST should therefore comprise an increased specificity for KIT while at the same time displaying a reduced ability to inhibit ABL1.
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Rausch
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA, USA.|Current address: Department of Pathology, Kazan State Medical University, Kazan, Russia.
authors.forename: Sergei
authors.initials: S
authors.lastname: Boichuk
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA, USA.
authors.forename: Areej A
authors.initials: AA
authors.lastname: Ali
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA, USA.
authors.forename: Sneha S
authors.initials: SS
authors.lastname: Patil
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA, USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Liu
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Lee
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA, USA.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Brown
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA, USA.
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Makielski
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Anatomy, Kochi Medical School, Nankoku Kochi, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Taguchi
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Shih-Fan
authors.initials: SF
authors.lastname: Kuan
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA, USA.|Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Anette
authors.initials: A
authors.lastname: Duensing
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D046888:Tissue Array Analysis
chemical_list: D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D016315:Proto-Oncogene Proteins c-abl
keywords: ABL1; KIT; gastrointestinal stromal tumor (GIST); imatinib mesylate