Targeting FSP1 to induce ferroptosis in chromophobe renal cell carcinoma

Abstract

There are no proven therapies for metastatic or unresectable Chromophobe Renal Cell Carcinoma (ChRCC). ChRCC is characterized by high glutathione levels and hypersensitivity to ferroptosis, an iron-dependent form of cell death characterized by peroxidation of polyunsaturated fatty acids. The underlying mechanisms leading to ferroptosis hypersensitivity are unknown. Ferroptosis suppressor protein (FSP1) is a glutathione-independent suppressor of ferroptosis whose role in ChRCC is unexplored. In The Cancer Genomic Atlas (TCGA), we find that ChRCC exhibits the second highest upregulation of FSP1 relative to healthy organ out of all cancers, and that higher FSP1 expression correlates with poorer patient outcomes. We also define a ferroptosis signature combining FSP1 and Solute Carrier Family 7 Member 11 (SLC7A11) that predicts patient survival across all TCGA tumor types. Data queried from the Dependency Map and the Cancer Target Discovery and Development indicate that high FSP1 expression correlates with resistance to cell death induced by disruption of glutathione homeostasis via inhibition of glutathione peroxidase 4 (GPX4) or SLC7A11. Studies using ChRCC cell lines in vitro reveal that genetic inhibition of GPX4 or FSP1 individually does not induce substantial cell death, while inhibition of both results in near-complete loss of viability. Consistent with these genetic data, combining pharmacologic inhibition of GPX4 or SLC7A11 with inhibition of FSP1 demonstrates synergistic loss of viability. Strikingly, inhibition of FSP1 alone in vivo is sufficient to decrease ChRCC tumor growth by 69%, consistent with recent studies in lung and colorectal cancer showing similar effects. Taken together, these data establish FSP1 as targetable vulnerability in ChRCC.