Purpose: Advanced/metastatic forms of clear cell Renal Cell Carcinomas (ccRCCs) have limited therapeutic options. Genome-wide genetic screens have identified cellular dependencies in many cancers. Using the Broad Institute/Novartis’ combined shRNA dataset, and cross-validation with the CRISPR/Cas9 DepMap (21Q3) dataset, we sought therapeutically actionable dependencies in kidney lineage cancers. Experimental Design: We identified preferential genetic dependencies in kidney cancer cells versus other lineages. BCL2L1, which encodes the BCL-XL anti-apoptotic protein, scored as the top actionable dependency. We validated this finding using genetic and pharmacological tools in a panel of ccRCC cell lines. Select BCL-XL-dependent (versus independent) cell lines were then transcriptionally profiled to identify biomarkers and mechanistic drivers of BCL-XL dependence. Cell-based studies (in vitro and in vivo) and clinical validations were used to address physiological relevance. Results: Inactivation of BCL-XL, but not BCL-2, led to fitness defects in renal cancer cells, and sensitized them to chemotherapeutics. Transcriptomic profiling identified a ‘BCL-XL dependency’ signature, including an elevated mesenchymal gene signature. A mesenchymal state was both necessary and sufficient to confer increased BCL-XL dependence. The ‘BCL-XL dependency’ signature was observed in ~30% of human ccRCCs, which were also associated with worse clinical outcomes. Finally, an orally bioavailable BCL-XL inhibitor, A-1331852, showed anti-tumor efficacy in vivo. Conclusions: Our studies uncovered an unexpected link between cell state and BCL-XL dependence in ccRCC. Therapeutic agents that specifically target BCL-XL are available. Our work justifies testing the utility of BCL-XL blockade to target, likely, a clinically aggressive subset of human kidney cancers.

Genome-wide genetic screens have identified cellular dependencies in many cancers. Using the Broad Institutes Achilles shRNA screening dataset, we mined for targetable dependencies by cell lineage. Our studies identified a strong dependency on BCL2L1, which encodes the BCL-XL anti-apoptotic protein, in a subset of kidney cancer cells. Genetic and pharmacological inactivation of BCL-XL, but not the related anti-apoptotic proteins BCL-2, led to fitness defects in renal cancer cells, and also sensitized them to chemotherapeutics. Neither BCL-XL levels (absolute or normalized to BCL-2) nor the status of the VHL gene, which is frequently mutated in kidney cancer, predicted BCL-XL dependence. Transcriptional profiling, however, identified a BCL-XL dependency mRNA signature, which included elevated mesenchymal gene expression in BCL-XL dependent cells. Promoting mesenchymal transition increased BCL-XL dependence; whereas, conversion to a more differentiated state overcame BCL-XL dependence in kidney cancer cells. The BCL-XL dependency mRNA signature was observed in almost a third of human clear cell Renal Cell Carcinomas (ccRCCs), which were also associated with worse clinical outcomes. Finally, an orally bioavailable BCL-XL inhibitor, A-1331852, showed anti-tumor efficacy in vivo. Altogether, our studies uncovered an unexpected link between cancer cell state and dependence on the anti-apoptotic BCL-XL protein and justify further testing on BCL-XL blockade as a potential way to target a clinically aggressive subset of human kidney cancers.

Supplementary Table from A Mesenchymal Tumor Cell State Confers Increased Dependency on the BCL-X_L Antiapoptotic Protein in Kidney Cancer