BCL-X _L Dependence is a Subtype Agnostic Actionable Feature of Difficult-to-Treat Kidney Cancers

The BCL-X_L anti-apoptotic protein is a clear cell Renal Cell Carcinoma (ccRCC) dependency; however, the mechanism of this dependence and its relevance in other aggressive kidney cancer contexts, including metastatic and/or rare RCC subtypes [e.g., Fumarate Hydratase (FH)-deficient and sarcomatoid RCCs], is unknown. Computational predictions, using a machine learning model trained on the human RCC TCGA dataset, and cell-based validations, confirmed BCL-X_L dependence in all RCC subtypes. Remarkably, cell state changes, 'anoikis' programs, inflammatory state, and metabolic perturbations (e.g., fumarate production in FH-deficient RCCs) independently conferred increased BCL-X_L dependence. Correlation studies revealed that increased AMPK isoform 2 (<i>PRKAA2</i>) expression is a kidney-specific biomarker of BCL-X_L dependence. Indeed, pharmacological AMPK activation sensitized RCCs to BCL-X_L blockade. Finally, using functional studies, we developed a multivariate model that accurately predicted BCL-X_L dependence in RCC. Our studies offer biomarkers for patient stratification and credential BCL-X_L as a subtype agnostic vulnerability in difficult-to-treat RCCs.