title: Inhibition of KIT-glycosylation by 2-deoxyglucose abrogates KIT-signaling and combination with ABT-263 synergistically induces apoptosis in gastrointestinal stromal tumor.
abstract: Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) is frequently used for visualizing gastrointestinal stromal tumors (GIST), which are highly glucose-avid tumors. Dramatic metabolic responses following imatinib treatment indicate a high, KIT-dependent glucose turnover which has been particularly helpful for predicting tumor response to imatinib. The glucose analogue 2-deoxyglucose (2DG) inhibits glucose metabolism in cancer cells that depend on aerobic glycolysis for ATP production. We show that 2DG inhibits proliferation in both imatinib-sensitive and imatinib-resistant GIST cell lines at levels that can be achieved clinically. KIT-negative GIST48B have 3-14-fold higher IC50 levels than KIT-positive GIST cells indicating that oncogenic KIT may sensitize cells to 2DG. GIST sensitivity to 2DG is increased in low-glucose media (110 mg/dl). 2DG leads to dose- and glucose dependent inhibition of KIT glycosylation with resultant reduction of membrane-bound KIT, inhibition of KIT-phosphorylation and inactivation of KIT-dependent signaling intermediates. In contrast to imatinib, 2DG caused ER-stress and elicited the unfolded protein response (UPR). Mannose but not pyruvate rescued GIST cells from 2DG-induced growth arrest, suggesting that loss of KIT integrity is the predominant effect of 2DG in GIST. Additive anti-tumoral effects were seen with imatinib and BH3-mimetics. Our data provide the first evidence that modulation of the glucose-metabolism by 2DG may have a disease-specific effect and may be therapeutically useful in GIST.
authors.affiliation: Dept. of Medical Oncology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; Sarcoma Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mühlenberg
authors.affiliation: Dept. of Medical Oncology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; Sarcoma Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Grunewald
authors.affiliation: Sarcoma Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; Dept. of Visceral and Transplant Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Treckmann
authors.affiliation: Sarcoma Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; Dept. of Visceral and Transplant Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Podleska
authors.affiliation: Dept. of Medical Oncology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schuler
authors.affiliation: Dept. of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
authors.affiliation: Dept. of Medical Oncology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; Sarcoma Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bauer
mesh_terms: D000814:Aniline Compounds / Q000819:agonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000819:agonists / Q000494:pharmacology*; D004357:Drug Synergism; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013449:Sulfonamides / Q000819:agonists / Q000494:pharmacology*
chemical_list: D000814:Aniline Compounds; D013449:Sulfonamides; D003847:Deoxyglucose; D019009:Proto-Oncogene Proteins c-kit; C528561:navitoclax