Abstract IA021: Chromophobe RCC: Therapeutic targeting of ferroptosis

Abstract Henske AACR abstract Chromophobe renal cell carcinoma (ChRCC) is the second most common non–clear cell RCC, with metastatic disease associated with a median overall survival of ∼2 years. ChRCC occurs sporadically and in individuals with Tuberous Sclerosis Complex (TSC) and Birt-Hogg-Dube syndrome (BHD). ChRCC is believed to arise from the specialized, mitochondria-rich intercalated cells of the distal nephron. The genetic hallmarks of ChRCC include 1) whole chromosome losses (including chromosomes 1, 2, 6, and 10), 2) one of the highest rates of mitochondrial DNA mutations (ND4, ND5) in the TCGA, and 3) a low rate of mutations in known oncogenes/tumor suppressors, with p53 mutations in about 30% and PTEN/TSC/mTOR mutations in about 10%. Using metabolomic profiling (PNAS 2018), we discovered that ChRCC have markedly elevated levels of glutathione (GSH) levels (50-100-fold higher than matched normal kidney). Surprisingly, given this high GSH, ChRCC-derived cell lines are hypersensitive to ferroptosis induced by blocking cystine import with IKE, thereby blocking GSH production, or inhibiting glutathione peroxidase 4 (GPX4) with RSL3 (PNAS 2022, Oncogene 2025). Ferroptosis is an iron-dependent form of cell death triggered by lipid peroxidation. The hypersensitivity to ferroptosis in ChRCC suggests that the elevated GSH is required to protect the cells from oxidative-stress induced death. Single cell RNA sequencing analyses (J Clin Oncol 2025) revealed that NRF2 signaling (which regulates oxidative stress responses) and ferroptosis are the top two upregulated pathways in ChRCC tumor cells when compared with intercalated cells from normal kidney. Taken together, these data suggest that induction of ferroptosis could have therapeutic efficacy in ChRCC. In TCGA data, ChRCC has the second highest expression of Ferroptosis suppressor protein 1 (FSP1) relative to the matched healthy organ. FSP1 is a glutathione independent suppressor of ferroptosis that acts by reducing co-enzyme Q10 and (ubiquinone) and vitamin K to their active, antioxidant forms. Inhibition of FSP1 in ChRCC cell lines acts synergistically with GSH-dependent ferroptosis inducers (IKE and RSL3) to induce ferroptotic death. Remarkably, in vivo, shRNA downregulation of FSP1 is sufficient to almost completely block tumor growth (Oncogene, 2025). In unpublished work, we have found that FSP1 is upregulated in ferroptosis-resistant ChRCC-derived cell lines. We are investigating the tumor immune microenvironment of the sarcomatoid variant of ChRCC, which is known to have higher metastatic potential. We have developed two new mouse models of ChRCC: a humanized mouse model a genetically engineered mouse model, in which knockout of Tsc2 leads to ChRCC-like tumors expressing the “hallmark” ChRCC genes including KIT. KIT is of special interest since ChRCC has the highest of KIT expression in the TCGA. KIT-targeted antibody drug conjugates represent a potential therapeutic direction. Citation Format: Elizabeth Henske. Chromophobe RCC: Therapeutic targeting of ferroptosis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr IA021.