Cánceres con Deficiencia de Succinato Deshidrogenasa Tienen Mayor Susceptibilidad al Daño del ADN Inducido por Ym155

The hereditary pheochromocytoma and paraganglioma (hPPGL) syndrome, caused by germline succinate dehydrogenase (SDHx) gene mutation, predisposes individuals to pheochromocytomas (Pheo), paragangliomas (PGL), renal cell carcinoma (RCC), and gastrointestinal stromal tumors (GIST). Notably, tumors with succinate dehydrogenase subunit B (SDHB) deficiency demonstrate increased metastatic risk and current systemic treatments remain only palliative. Hence, discovering novel therapeutic avenues to improve SDHB-cancer prognosis is an urgent need. Here we leveraged human SDHB-deficient UOK269 RCC cells (SDHB-KO) and isogenic SDHB-reconstituted control cells (SDHB-WT) to discover SDH-dependent mitochondria-directed cytotoxic agents. Given the reduced ATP-generating capacity of SDHB-KO cells, we hypothesized they would be uniquely sensitive to futile cycle induction with mitochondrial ionophores. Indeed, ionophores exhibited preferential cytotoxicity toward SDHB-KO cells. However, the mitochondria-directed chemotherapeutic compound Ym155 demonstrated more potent and dramatic preferential cytotoxicity towards SDHB-KO cells. Importantly, SDH-dependent cytotoxicity of Ym155 was validated in multiple cell models, including primary human pheochromocytoma cells, a mouse pheochromocytoma (MPC) cell line and primary SDHB-deficient mouse kidney cells. Notably, genetic evidence of Ym155 synthetic lethality with SDHB-deficiency was buttressed in additional cell models using two chemical inhibitors of SDH enzyme activity. Mechanistically, SDH-deficiency sensitized cells to Ym155-induced DNA damage. Strikingly, SDH-dependent Ym155 sensitivity was recapitulated by inhibition of the histone demethylase KDM4, a downstream consequence of SDH deficiency. In summary, accumulation of succinate in SDH-deficient tumors inhibited KDM4 activity, impaired DNA repair and yielded enhanced susceptibility to Ym155-induced reactive oxygen species (ROS) generation. The identified intrinsic susceptibilities of SDHB-deficient cancers have the potential to be therapeutically leveraged.