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bioRxiv · 10.64898/2025.12.10.693422

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.
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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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Basuroy, T., Grubb, T., Sadagopan, A., Qin, X., Madison, K., Hall, A., Willard, B., Vanharanta, S., Sarosiek, K., Viswanathan, S. R., Chakraborty, A. A.. 2025-12-13. BCL-XL Dependence is a Subtype Agnostic Actionable Feature of Difficult-to-Treat Kidney Cancers. https://doi.org/10.64898/2025.12.10.693422

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