Proteogenomic discovery of -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 () 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 genomic defects and yet phenocopy the transcriptional profile of -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 genomic defects. In summary, our findings suggest that dysregulation of the RB pathway in cancers lacking genomic defects provides a molecular rationale for how these cancers could be treated.