BCL-XL dependence is a subtype agnostic actionable feature of difficult-to-treat kidney cancers

Abstract BCL-X L is a BCL-2 family anti-apoptotic protein that functions as a targetable dependency in clear cell Renal Cell Carcinoma (ccRCC), the most common form of adult kidney cancer. However, the mechanisms driving this dependence are unclear. Moreover, although significant strides have been made in managing ccRCC, advanced/metastatic cases of this disease and other rarer RCC subtypes [e.g., Fumarate Hydratase (FH)-deficient and sarcomatoid tumors] lack durable therapies and have poor clinical outcomes. Here, we interrogated the mechanisms and extent of BCL-X L dependence to address its potential therapeutic utility in clinically challenging cases of kidney cancer. In a panel of physiologically relevant cell lines representing several RCC subtypes, we used pharmacological or genetic tools to perturb cell state and FH biology and measured the impact of these perturbations on response to pharmacological BCL-X L inhibition. Simultaneously, in vivo studies addressed the importance of BCL-X L blockade in metastatic RCC. Finally, using a machine-learning model trained on the human RCC TCGA dataset called ‘Transcriptional Prediction of Lethality (TrPLet)’, we computationally predicted and then validated BCL-X L dependence in all RCC subtypes. This analysis identified the cellular determinants of BCL-X L dependence, including high expression of BCL-X L , CD44, and NOXA. We found that disparate biological programs, such as cell state changes, an ‘anoikis’-like program, inflammatory state, and metabolic perturbations (e.g., fumarate production in FH-deficient RCCs) – which converge directly or indirectly on AMPK activation – conferred increased BCL-X L dependence in various RCC subtypes. Remarkably, correlation studies using the DepMap dataset revealed that increased AMPK isoform 2 ( PRKAA2 ) expression was a kidney lineage-specific biomarker of BCL-X L dependence. Indeed, pharmacological AMPK activation sensitized RCCs to BCL-X L blockade. Altogether, our work offers mechanistic insights on BCL-X L dependence and establishes a biomarker panel for patient stratification to ultimately credential BCL-X L as a subtype agnostic vulnerability in difficult-to-treat RCCs.