Deficiency Enhances Tumor Progression via ERBB3 Signaling in -Rearranged Renal Cell Carcinoma.

-rearranged Renal Cell Carcinoma (TFE3-RCC) is an aggressive subtype of RCC characterized by Xp11.2 rearrangement, leading to TFE3 fusion proteins with oncogenic potential. Despite advances in understanding its molecular biology, effective therapies for advanced cases remain elusive. This study investigates the role of , a component of the SWI/SNF chromatin remodeling complex, in TFE3-RCC. Through a series of in vitro and in vivo experiments, we confirmed that acts as a tumor suppressor in TFE3-RCC. knockout (KO) enhanced TFE3-RCC cell migration, proliferation, and tumor growth. Transcriptomic analysis revealed ERBB3 as a key target gene regulated by both PRCC-TFE3 and . Chromatin immunoprecipitation (ChIP) assays demonstrated that PRCC-TFE3 directly binds to and upregulates ERBB3 expression, with KO further enhancing this effect. TFE3-RCC KO cells exhibited significant gene expression enrichment in MAPK and ERBB3 signaling pathways. These cells also showed increased activation of ERBB3, EGFR, and selective activation of SRC and MAPK. TFE3-RCC KO cells demonstrated heightened sensitivity to the ERBB3 inhibitor AZD8931 compared to their wild-type counterparts, exhibiting significantly reduced migration and proliferation rates. These findings suggest that the PRCC-TFE3--ERBB3 axis plays a critical role in TFE3-RCC pathogenesis and highlights the potential of targeting ERBB3 in -deficient TFE3-RCC as a therapeutic strategy. This study provides new insights into the molecular mechanisms of TFE3-RCC and suggests avenues for precision treatment of this aggressive cancer.