Abstract PR013: An integrative genomics approach converges on a critical OXPHOS program driven by MiT/TFE fusions in translocation renal cell carcinoma

Abstract Translocation renal cell carcinoma (tRCC) is a rare and aggressive subtype of non-clear cell renal cell carcinoma (RCC) that represents 1-5% of kidney cancer in adults. Biologically, tRCC is driven by rearrangements that involve a member of the MiT/TFE transcription factor gene family, most commonly TFE3. There are currently no molecularly-targeted therapies specific to tRCC, owing in part to an incomplete mechanistic understanding of precisely how MiT/TFE gene fusions exert their oncogenic function. In prior work, we leveraged “histologic overlap” between tRCC and other RCC subtypes to identify tRCC cases from across multiple genomic, clinical trial, and retrospective RCC datasets, with the goal of defining the molecular landscape of this disease. Here, by analyzing pathways selectively activated in tRCC relative to other RCC subtypes in this aggregate dataset, we observed that tRCCs display strong enrichment for genes involved in oxidative phosphorylation (OXPHOS), reactive oxidative species (ROS) sensing, and the response to oxidative stress mediated by the transcription factor NRF2 (nuclear factor erythroid-derived2-like 2 [NFE2L2]). We performed chromatin immunoprecipitation and sequencing (ChIP-Seq) on a panel of tRCC and clear-cell RCC (ccRCC) cell lines, using antibodies against TFE3 as well as the active enhancer mark H3K27ac. We found that tRCC cell lines display a distinctive epigenomic profile characterized by activation of a host of genes involved in driving OXPHOS as well as NRF2 signaling. We further found that TFE3 fusions and NRF2 physically interact and genomically co-localize at multiple genes critical for mediating the response to antioxidant stress, suggesting that this metabolic phenotype is transcriptionally driven by TFE3 fusions. Genome-scale CRISPR screening in tRCC cell lines subsequently revealed tRCC-selective vulnerabilities in components of the OXPHOS machinery and in the NRF2 pathway, a distinction from most other kidney cancers in which aerobic glycolysis predominates. Overall, our genomic and functional studies implicate an essential transcriptional program driven by TFE3 fusions that converges on activation of the OXPHOS and NRF2 pathways. These molecular features provide mechanistic rationale for exploring the therapeutic targeting of OXPHOS and/or redox homeostasis pathways in tRCC. Citation Format: Jiao Li, Danny S. Gallant, Ananthan Sadagopan, Bingchen Li, Qingru Xu, Srinivas R. Viswanathan. An integrative genomics approach converges on a critical OXPHOS program driven by MiT/TFE fusions in translocation renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr PR013.