BCL-XL Dependence is a Subtype Agnostic Actionable Feature of Difficult-to-Treat Kidney Cancers
Basuroy, T.; Grubb, T.; Sadagopan, A.; Qin, X.; Madison, K.; Hall, A.; Willard, B.; Vanharanta, S.; Sarosiek, K.; Viswanathan, S. R.; Chakraborty, A. A.
Show abstract
The BCL-XL 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-XL 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-XL dependence. Correlation studies revealed that increased AMPK isoform 2 (PRKAA2) expression is a kidney-specific biomarker of BCL-XL dependence. Indeed, pharmacological AMPK activation sensitized RCCs to BCL-XL blockade. Finally, using functional studies, we developed a multivariate model that accurately predicted BCL-XL dependence in RCC. Our studies offer biomarkers for patient stratification and credential BCL-XL as a subtype agnostic vulnerability in difficult-to-treat RCCs.
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