Treatment options for clear-cell renal cell carcinomas (ccRCC) in their advanced or metastatic stages are limited. Many malignancies have been found to have cellular dependencies through genome-wide genetic screening. Researchers searched for therapeutically actionable dependencies in kidney lineage tumors using the Broad Institute/Novartis combined short hairpin RNA (shRNA) dataset and cross-validation with the CRISPR/Cas9 DepMap (21Q3) dataset. Here, they reported the discovery of genetic dependencies that are disproportionately prevalent in kidney cancer cells. The antiapoptotic BCL-XL protein is encoded by the gene BCL2L1, which was shown to be the most important operable dependence. 

Using genetic and pharmacologic methods, they confirmed this result in a variety of ccRCC cell lines. Transcriptional profiling was subsequently used to uncover biomarkers and molecular drivers of BCL-XL reliance on a subset of BCL-XL dependent (vs independent) cell lines. Physiological relevance was investigated using in vitro and in vivo cell-based research, as well as clinical validations. Fitness deficits and chemosensitivity in renal cancer cells were caused by BCL-XL inactivation, but not BCL-2. An increased mesenchymal gene signature was part of a “BCL-XL dependence” signature discovered by transcriptomic profiling. 

The increased reliance on BCL-XL was not only possible but also required a mesenchymal condition. About 30% of human ccRCCs exhibited the “BCL-XL dependence” profile, and these tumors were linked to poorer clinical outcomes. A-1331852, a BCL-XL inhibitor that can be taken orally, has demonstrated anticancer activity in vivo. This research revealed an unanticipated dependency of ccRCC on BCL-XL. There are now accessible therapeutic medicines that directly target BCL-XL. Our findings support further investigation into the potential of BCL-XL inhibition for treating a subset of clinically aggressive human kidney malignancies.