Succinate Mediates Tumorigenic Effects Succinate Receptor 1: Potential for New Targeted Treatment Strategies in Succinate Dehydrogenase Deficient Paragangliomas

Paragangliomas and pheochromocytomas (PPGLs) are chromaffin tumors associated with severe catecholamine-induced morbidities. Surgical removal is often curative. However, complete resection may not be an option for patients with succinate dehydrogenase subunit A-D () mutations. mutations are associated with a high risk for multiple recurrent, and metastatic PPGLs. Treatment options in these cases are limited and prognosis is dismal once metastases are present. Identification of new therapeutic targets and candidate drugs is thus urgently needed. Previously, we showed elevated expression of succinate receptor 1 () in PPGLs and head and neck paragangliomas. Its ligand succinate has been reported to accumulate due to mutations. We thus hypothesize that autocrine stimulation of SUCNR1 plays a role in the pathogenesis of mutation-derived PPGLs. We confirmed elevated SUCNR1 expression in PPGLs and after knockout in progenitor cells derived from a human pheochromocytoma (hPheo1). Succinate significantly increased viability of -transfected PC12 and ERK pathway signaling compared to control cells. Candidate inhibitors successfully reversed proliferative effects of succinate. Our data reveal an unrecognized oncometabolic function of succinate in PPGLs, providing a growth advantage .