OS-RC-2

Background

This study identifies PBRM1 loss as a biomarker of increased sensitivity to MCL1 and CDK9 inhibition in clear cell renal cell carcinoma (ccRCC). CRISPR dependency analysis showed PBRM1-mutant ccRCC cells are dependent on MCL1. The MCL1 inhibitor PRT1419 and CDK9 inhibitor PRT2527 inhibited spheroid growth and induced apoptosis in PBRM1-deficient models, but not PBRM1-wild-type. PBRM1 loss correlated with pro-apoptotic priming, including NOXA upregulation. PRT1419 and PRT2527 synergized with sunitinib, everolimus, pazopanib, cabozantinib, and belzutifan, supporting PBRM1 as a potential biomarker for MCL1/CDK9-targeted therapy in ccRCC.

Key Findings

Damaging PBRM1 mutations were associated with increased MCL1 dependency in ccRCC cell lines. The selective MCL1 inhibitor PRT1419 inhibited 3D spheroid growth and induced caspase-mediated apoptosis in PBRM1-mutant but not PBRM1-wild-type ccRCC models. PBRM1 depletion by RNAi or knockout in wild-type cells conferred sensitivity to PRT1419. Mechanistically, PBRM1 loss upregulated pro-apoptotic factors, notably NOXA, priming cells for apoptosis. In an OS-RC-2 PBRM1-mutant xenograft, PRT1419 produced 42% tumor growth inhibition. PRT1419 also synergized with sunitinib, everolimus, cabozantinib, pazopanib, and belzutifan. The CDK9 inhibitor PRT2527 depleted MCL1 and similarly inhibited PBRM1-deficient models, synergizing with sunitinib and reducing tumor regrowth in H1703 xenografts. These findings support PBRM1 loss as a predictive biomarker for MCL1/CDK9 inhibition in ccRCC.

Contribution

Creative Bioarray provided the OSRC-2 (CSC-C9232W) clear cell renal carcinoma cell line used in this study. This PBRM1-mutant model enabled in vitro sensitivity testing and the OS-RC-2 cell line-derived xenograft, which demonstrated PRT1419 antitumor activity. Thus, Creative Bioarray contributed a key preclinical ccRCC model for validating MCL1 inhibition.