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 (110mg/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.

Low carbohydrate diet prevents Mcl-1-mediated resistance to BH3-mimetics

“…We therefore conclude that a Low CHO diet is a more robust and efficient way to decrease Mcl-1 expression and it is very likely to be the main component, albeit not the unique involved in this effect. This conclusion is also supported by the widely described effects of glycolytic inhibitors on Mcl-1 expression and on the sensitization toward ABT-737 [4, 15–17, 20]. Altogether our results indicate that lowing circulating glucose is a key event in the decrease of Mcl-1 expression.…”

VHL-deficient renal cancer cells gain resistance to mitochondria-activating apoptosis inducers by activating AKT through the IGF1R-PI3K pathway

“…Following our publication on the 2DG-ABT combination treatment in 2011, the same combination has been tested on gastrointestinal stromal tumors (GIST) by Muhlenberg and colleagues [16]. Because these tumors have highly elevated glucose uptake, they are ideal candidates for 2DG-ABT combination therapy.…”

Gastrointestinal stromal tumors (GIST): Facing cell death between autophagy and apoptosis

“…Peginterferon alfa-2b ! in combination with imatinib to restore drug sensitivity via the downregulation of the MTOR pathway [86]. 2DG C ABT263 !…”

“…Overall, this indicates a high KIT-dependent glucose turnover, allowing early prediction of tumor response to imatinib by PET. 86,87 Tarn and colleagues observed a significant reduction in glucose uptake in imatinib-treated GIST cells, mediated by a decrease of the glucose transporter SLC2A4/GLUT4. 78 The authors also showed that glucose uptake in GIST cells, evaluated via FDG-PET, occurs in an AKT-signaling-dependent manner in both imatinib-sensitive and resistant cell models, as constitutively .…”

“…78 M€ uhlenberg and coworkers also investigated the disruption of glucose metabolism as a therapeutic approach in GIST. 86 The authors used 2-deoxyglucose (2DG), a non-metabolizable glucose analog, to show inhibition of KIT glycosylation, which abrogates KIT signaling. Additionally, the combination of 2DG with imatinib and ABT263, an antagonist of the anti-apoptotic BCL2 protein, may enhance the apoptotic response.…”