American Association for Cancer Research
10780432ccr172697-sup-189356_2_supp_4415083_p03834.pdf (395.61 kB)

Supplemental Figure 5 from Mitochondrial Inhibition Augments the Efficacy of Imatinib by Resetting the Metabolic Phenotype of Gastrointestinal Stromal Tumor

Download (395.61 kB)
journal contribution
posted on 2023-03-31, 19:41 authored by Gerardo A. Vitiello, Benjamin D. Medina, Shan Zeng, Timothy G. Bowler, Jennifer Q. Zhang, Jennifer K. Loo, Nesteene J. Param, Mengyuan Liu, Alec J. Moral, Julia N. Zhao, Ferdinand Rossi, Cristina R. Antonescu, Vinod P. Balachandran, Justin R. Cross, Ronald P. DeMatteo

HIF1a mRNA expression in KitV558del/+ mice and 72h cell viability assay of GIST-T1 cells treated with ferric iron chloride + VLX600




Sloan Kettering Institute Laboratory of Comparative Pathology, Molecular Cytology, The Donald B. and Catherine C. Marron Cancer Metabolism Center, Antitumor Assessment core facility, and Research Animal Resource Center



Purpose: Imatinib dramatically reduces gastrointestinal stromal tumor (GIST) 18F-FDG uptake, providing an early indicator of treatment response. Despite decreased glucose internalization, many GIST cells persist, suggesting that alternative metabolic pathways are used for survival. The role of mitochondria in imatinib-treated GIST is largely unknown.Experimental Design: We quantified the metabolic activity of several human GIST cell lines. We treated human GIST xenografts and genetically engineered KitV558del/+ mice with the mitochondrial oxidative phosphorylation inhibitor VLX600 in combination with imatinib and analyzed tumor volume, weight, histology, molecular signaling, and cell cycle activity. In vitro assays on human GIST cell lines were also performed.Results: Imatinib therapy decreased glucose uptake and downstream glycolytic activity in GIST-T1 and HG129 cells by approximately half and upregulated mitochondrial enzymes and improved mitochondrial respiratory capacity. Mitochondrial inhibition with VLX600 had a direct antitumor effect in vitro while appearing to promote glycolysis through increased AKT signaling and glucose transporter expression. When combined with imatinib, VLX600 prevented imatinib-induced cell cycle escape and reduced p27 expression, leading to increased apoptosis when compared to imatinib alone. In KitV558del/+ mice, VLX600 alone did not induce tumor cell death, but had a profound antitumor effect when combined with imatinib.Conclusions: Our findings show that imatinib alters the metabolic phenotype of GIST, and this may contribute to imatinib resistance. Our work offers preclinical proof of concept of metabolic targeting as an effective strategy for the treatment of GIST. Clin Cancer Res; 24(4); 972–84. ©2017 AACR.

Usage metrics

    Clinical Cancer Research



    Ref. manager