Identification of a Key Regulator of Mitochondrial Metabolism, the Lrpprc Protein as a Novel Therapeutic Target in Sdha Overexpressing Ovarian Tumors

Ovarian cancer is the deadliest of all gynecologic malignancies due to limited therapeutic options. Our data show that tumor-specific metabolism of ovarian cancer could be effectively targetable, which highlights a path for new anti-cancer therapies. Our work showed that the upregulation of mitochondrial enzyme SDHA is particularly prevalent in ovarian carcinoma. The SDHA overexpression significantly induced orthotopic ovarian tumor growth substantially reducing mouse survival. We showed that the SDHA overexpressing tumors depend on glutaminolysis, and increased activity of TCA cycle coupled with mitochondrial oxidative phosphorylation (OXPHOS), which are essential for high-energy metabolism and cell survival. We also identified a distinctive vulnerability of SDHA overexpressing tumors to agents targeting regulators of OXPHOS pathway, particularly LRPPRC protein. LRPPRC is a key regulator of mitochondria homeostasis and energy metabolism promoting OXPHOS and ATP generation, however when overexpressed, the LRPPRC acts as tumor oncogene. Our analysis of SDHA and LRPPRC gene and protein expression patterns in precursor lesions and established ovarian cancer demonstrated that the upregulation of SDHA is accompanied by LRPPRC overexpression, particularly in advanced tumors. Our novel findings highlight for the first time a potential functional interaction between SDHA and LRPPRC in development and progression of ovarian malignancy. Importantly, our in vivo data showed that pharmacological blocking LRPPRC function results in a long-term therapeutic benefit and can be an effective therapy in SDHA and LRPPRC overexpressing ovarian tumors. Overall, our study underlines an understudied role of concomitant overexpression of SDHA and LRPPRC in ovarian cancer pathogenesis highlighting new opportunities for therapeutic intervention.