BCL-xL dependency in chromophobe renal cell carcinoma.

Chromophobe renal cell carcinoma (ChRCC) is the third most common subtype of kidney cancer, with limited therapeutic options. Using BH3 profiling to screen ChRCC-derived cell lines, we discovered that BH3 peptides targeting BCL-xL promote apoptosis in ChRCC. Downregulation of BCL2L1 is sufficient to induce apoptosis in ChRCC-derived cells, consistent with our screening results. BCL2L1, encoding BCL-xL, is fourfold upregulated in ChRCC compared to normal kidney and has the second highest expression in The Cancer Genome Atlas. BCL2L1 downregulation enhances MCL-1 expression, suggesting a possible compensatory role for MCL-1. Based on these results, we evaluated two BH3 mimetics, A-1331852 (targeting BCL-xL) and S63845 (targeting MCL-1). Their combination resulted in 80% cell death. DT2216, a proteolysis-targeting chimera (PROTAC) that targets BCL-xL for degradation, induced cleaved PARP and caspase 3, indicators of apoptosis. ChRCC cells are known to be highly sensitive to ferroptosis. We combined A-1331852 and S63845 with IKE or RSL3 (ferroptosis-inducing drugs). BCL-xL and MCL-1 inhibition enhanced the susceptibility to ferroptosis, suggesting a link between apoptosis and ferroptosis in ChRCC. These data indicate that BCL-xL maintains ChRCC cell survival by suppressing apoptosis. The BCL-xL-specific PROTAC DT2216, currently in clinical trials, may provide an opportunity for ChRCC therapy.