Abstract PR001: TFE3 fusions link tryptophan metabolism to AhR activation in tRCC: a targetable vulnerability

Abstract In 2024, an estimated 85,000 people in the United States will be diagnosed with tumors of the kidney and renal pelvis, with a disproportionately high incidence reported in Texas. Among kidney cancer subtypes, translocation renal cell carcinoma (tRCC) warrants particular attention: it accounts for ∼30% of pediatric cases, is the most common type in adolescents, carries a poor prognosis, and is uniformly lethal when metastatic, yet lacks disease-specific treatment protocols. Building on our recent work demonstrating that common TFE3 fusions (PRCC-, ASPSCR1-, and SFPQ-TFE3) converge on a shared gene-activation program that drives proliferation, migration, and invasion (Lyons et al., Cell, 2025), we sought to identify the downstream effector pathway(s) that mechanistically link fusion oncoproteins to malignant phenotypes. Using patient-derived, fusion-positive tRCC models, we integrated transcriptomic (RNA-seq), epigenomic (chromatin profiling of the aryl hydrocarbon receptor, AhR, and target loci), metabolomic interrogation of tryptophan (Trp) catabolism, and functional proliferation/migration/invasion assays coupled to genetic perturbation, rescue, and pharmacologic inhibition. These orthogonal approaches converge on AhR as a critical, ligand-dependent effector of TFE3 fusions. Across models, TFE3 fusion knockdown decreased endogenous Trp-derived AhR agonists (e.g., kynurenine-pathway metabolites), reduced AhR chromatin occupancy and transcriptional output, and suppressed malignant cellular behaviors. Strikingly, supplementation with AhR agonists restored AhR occupancy, target-gene activation, and proliferation/migration/invasion despite fusion knockdown, indicating that ligand sufficiency is sufficient to re-engage the program. Conversely, pharmacologic AhR blockade phenocopied fusion knockdown across multiple fusion backgrounds, supporting pathway dependence; notably, fusion-positive cells exhibited heightened sensitivity to structurally distinct AhR inhibitors consistent with an AhR dependency. Together, these data establish a direct mechanistic link between TFE3 fusions and ligand-driven AhR activation, position elevated production of endogenous AhR agonists as the biochemical engine coupling fusions to malignant behavior, and nominate AhR signaling as a defining, targetable dependency in tRCC, providing a strong rationale for therapeutic inhibition of the AhR axis in fusion-positive disease. Citation Format: Xiang Li, Gopinath Prakasam Prakasam, James Brugarolas, Benjamin R. Sabari. TFE3 fusions link tryptophan metabolism to AhR activation in tRCC: a targetable vulnerability [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl):Abstract nr PR001.