Proteogenomic discovery of <i>RB1</i> -defective phenocopy in cancer predicts disease outcome, response to treatment, and therapeutic targets

Genomic defects caused by truncating mutations or deletions in the Retinoblastoma tumor suppressor gene (<i>RB1</i>) are frequently observed in many cancer types leading to dysregulation of the RB pathway. Here, we propose an integrative proteogenomic approach that predicts cancers with dysregulation in the RB pathway. A subset of these cancers, which we term as "RBness," lack <i>RB1</i> genomic defects and yet phenocopy the transcriptional profile of <i>RB1</i>-defective cancers. We report RBness as a pan-cancer phenomenon, associated with patient outcome and chemotherapy response in multiple cancer types, and predictive of CDK4/6 inhibitor response in estrogen-positive breast cancer. Using RNA interference and a CRISPR-Cas9 screen in isogenic models, we find that RBness cancers also phenocopy synthetic lethal vulnerabilities of cells with <i>RB1</i> genomic defects. In summary, our findings suggest that dysregulation of the RB pathway in cancers lacking <i>RB1</i> genomic defects provides a molecular rationale for how these cancers could be treated.