Abstract A52: Overcoming mitochondrial oxidative phosphorylation-mediated resistance to targeted therapies in melanoma

Abstract

Abstract There is a critical need to understand and overcome resistance to targeted therapy in cancer. While FDA-approved BRAF and MEK inhibitors achieve clinical responses in the majority of metastatic melanoma patients with a BRAFV600 mutation, a significant proportion of patients have minimal responses, and virtually all patients develop acquired resistance in a short period of time. We and others have shown that increased oxidative phosphorylation (OxPhos), which is critically dependent on the transcriptional co-activator PGC1α, can mediate de novo resistance to MAPK pathway inhibitors in melanomas with BRAFV600 mutations. We have also demonstrated that elevated OxPhos (a) mediates de novo resistance to MEK inhibitors in melanoma cell lines without BRAFV600 mutations; (b) characterizes 30-50% of BRAFV600-mutant cell lines and patients with acquired resistance to BRAF +/- MEK inhibitors; and (c) predicts sensitivity to dual inhibition of mTORC1/2 in vitro and in vivo. Inhibition of mTORC1/2 downregulates both PGC1α and OxPhos through a novel mechanism involving the subcellular localization of the transcription factor MITF. To further exploit the therapeutic potential of targeting OxPhos, we have evaluated the molecular and anti-melanoma activities of a novel OxPhos inhibitor, IACS-10759, developed at M.D. Anderson Cancer Center. IACS-10759 potently inhibits the electron transport chain Complex I of mitochondrial OxPhos at low nanomolar concentrations. Additionally, this molecule has favorable safety and pharmacokinetic profile in animal models. Normal melanocytes, skin fibroblasts and most melanoma cell lines were not sensitive to micromolar doses of IACS-10759. However, a subset of de novo and acquired resistant melanomas with high OxPhos were sensitive to low nanomolar concentrations of IACS-10759 and underwent apoptotic cell death with treatment. An additional subset of melanomas were sensitive to the combination of IACS-10759 with MEK or BRAF inhibitors. Early functional studies revealed AMPK-activation associated effects as mediators of sensitivity, in addition to the inability of the cells to use alternate metabolic pathways for energy generation. Our findings demonstrate that a high OxPhos metabolic phenotype is associated with de novo and acquired resistance to MAPK pathway targeted therapies in melanoma, and support that targeting mTORC1/2 and the OxPhos complex 1 are promising strategies for counteracting this resistance. Citation Format: Vashisht Gopal Yennu-Nanda, Zeping Hu, Victoria M. Thiele, Tim Heffernan, Maria DiFrancesco, Joe Marszalek, Ralph Deberadinis, Michael A. Davies. Overcoming mitochondrial oxidative phosphorylation-mediated resistance to targeted therapies in melanoma. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A52.