Abstract IA08: Elevated endogenous SDHA drives pathologic metabolism in highly metastatic uveal melanoma

Abstract

Abstract Purpose: Metastatic uveal melanoma (UM) has a very poor prognosis and no effective therapy. Despite remarkable advances in treatment of cutaneous melanoma, UM remains recalcitrant to chemotherapy, small-molecule kinase inhibitors, and immune-based therapy. Experimental Design: We assessed two sets of oxidative phosphorylation (OxPhos) genes within 9,858 tumors across 31 cancer types. An OxPhos inhibitor was used to characterize differential metabolic programming of highly metastatic monosomy 3 (M3) UM. Seahorse analysis and global metabolomics profiling were done to identify metabolic vulnerabilities. Analyses of UM TCGA data set were performed to determine expressions of key OxPhos effectors in M3 and non M3 UM. We used targeted knockdown of succinate dehydrogenase A (SDHA) to determine the role of SDHA in M3 UM in conferring resistance to OxPhos inhibition. Results: We identified UM as having among the highest median OxPhos levels and showed that M3 UM exhibits a distinct metabolic profile. M3 UM shows markedly low succinate levels and has highly increased levels of SDHA, the enzyme that couples the TCA cycle with OxPhos by oxidizing (lowering) succinate. We show that SDHA-high M3 UM has elevated expression of key OxPhos molecules, exhibits abundant mitochondrial reserve respiratory capacity, and is resistant to OxPhos antagonism, which can be reversed by SDHA knockdown. Conclusions: Our study has identified a critical metabolic program within poor prognostic M3 UM. In addition to the heightened mitochondrial functional capacity due to elevated SDHA, M3 UM SDHA-high mediates resistance to therapy that is reversible with targeted treatment. Citation Format: Chandrani Chattopadhyay, Junna Oba, Jason Roszik, Scott E. Woodman, Elizabeth A. Grimm. Elevated endogenous SDHA drives pathologic metabolism in highly metastatic uveal melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA08.