Mitochondrial Inhibition Augments the Efficacy of Imatinib by Resetting the Metabolic Phenotype of Gastrointestinal Stromal Tumor

Abstract

Imatinib dramatically reduces gastrointestinal stromal tumor (GIST) F-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. We quantified the metabolic activity of several human GIST cell lines. We treated human GIST xenografts and genetically engineered mice with the mitochondrial oxidative phosphorylation inhibitor VLX600 in combination with imatinib and analyzed tumor volume, weight, histology, molecular signaling, and cell cycle activity. assays on human GIST cell lines were also performed. 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 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 mice, VLX600 alone did not induce tumor cell death, but had a profound antitumor effect when combined with imatinib. 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. .

Oxidative phosphorylation as a potential therapeutic target for cancer therapy

“…As a common theme, targeted therapies with tyrosine kinase inhibitors can upregulate OXPHOS (Fig. a ), as this has been documented for BRAF inhibition in melanoma or cKIT inhibition in gastrointestinal stromal tumors, increasing their “addiction” to OXPHOS. As a result, BRAF inhibition can be combined with phenformin to reduce melanoma progression, and the cKIT inhibitor imatinib can be combined with VLX600 to control the growth of gastrointestinal stromal tumors in mouse models .…”

“…a ), as this has been documented for BRAF inhibition in melanoma or cKIT inhibition in gastrointestinal stromal tumors, increasing their “addiction” to OXPHOS. As a result, BRAF inhibition can be combined with phenformin to reduce melanoma progression, and the cKIT inhibitor imatinib can be combined with VLX600 to control the growth of gastrointestinal stromal tumors in mouse models . Yet another example is provided by the treatment of mantle cell lymphoma with the Bruton's tyrosine kinase inhibitor ibrutinib, resulting into a resistance‐associated reprogramming toward OXPHOS with consequent sensitization to the complex I inhibitor IACS‐010759 .…”

“…As a result, BRAF inhibition can be combined with phenformin to reduce melanoma progression, 48 and the cKIT inhibitor imatinib can be combined with VLX600 to control the growth of gastrointestinal stromal tumors in mouse models. 49 Yet another example is provided by the treatment of mantle cell lymphoma with the Bruton's tyrosine kinase inhibitor ibrutinib, resulting into a resistanceassociated reprogramming toward OXPHOS with consequent sensitization to the complex I inhibitor IACS-010759. 50 It is tempting to speculate that OXPHOS inhibitors can be advantageously combined with inhibitors of receptor tyrosine kinases, because such receptors are positive regulators of glucose uptake and glycolysis, [51][52][53] indicating that their inhibition cuts off essential bioenergetics supply.…”

Mitochondrial DNA Variations in Tumors: Drivers or Passengers?

“…The recent improvement of high-throughput drug-screening platforms allowed the identification of novel non-toxic mitochondrial inhibitors, as in the case of diphenyleneiodonium chloride (DPI), a strong inhibitor of mitochondrial complex I and II flavin-containing enzymes, which effectively depletes cancer stem-like cells (CSCs), one of the main drivers of poor clinical outcome in a wide variety of tumor types and especially in advanced disease states [103]. Interestingly, mitochondrial inhibition with VLX600 has also been proposed in combination with imatinib in the treatment of drug-resistant gastrointestinal stromal tumors (GISTs) [104].…”

Establishment of a Patient‐Derived Xenograft Tumor From Hepatitis C–Associated Liver Cancer and Evaluation of Imatinib Treatment Efficacy

“…When tumors were palpable, tumor-bearing mice were randomly divided into two groups for control (regular drinking water) or c-Kit inhibitor (imatinib) treatment given through drinking water (600 mg/L), as described earlier. (20) The imatinib-supplemented water was replaced every 3 days. Tumor growth was examined weekly until the end of each experiment.…”