Abstract 7037: Phospho-reprogramming mitochondrial respiration underlies sunitinib resistance in renal cell carcinoma.

Abstract Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. While surgery is effective for localized ccRCC, advanced disease necessitates the use of additional therapies such as immune checkpoint inhibitors or tyrosine kinase inhibitors (TKIs). Emergent resistance limits TKI efficacy, and prognosis in patients with refractory disease is poor. Recent work indicates that metabolic reprogramming underlies TKI resistance, however the details are poorly understood. Phosphoproteomics study has shown that sunitinib-resistant ccRCC tumors exhibit differential phosphorylation of the electron transport chain Complex II subunit SDHA and the mitochondrial chaperone TRAP1. TRAP1 controls metabolic flux by regulating the activity of the mitochondrial respiratory machinery, indicating a role for TRAP1 phosphorylation in tuning this activity. The objective of our work was to determine the impact of SDHA Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7037.