Reframing RB Tumor Suppressor Dysfunction as a Therapeutic Vulnerability in Cancer

The retinoblastoma (RB) protein was the first tumor suppressor discovered and has been extensively studied for its canonical role in cell-cycle regulation. However, RB has broader noncanonical roles in DNA damage repair, chromosomal stability, apoptosis control, lineage commitment, cell differentiation and broad transcriptional regulation. Historically, RB inactivation has been associated with tumorigenesis, as well as resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), leading to its investigation as a potential predictive biomarker. However, clinical data have not demonstrated that RB function reliably predicts response to CDK4/6i consistently. These discrepancies highlight the need to reconsider RB’s role in therapeutic response, as RB loss can promote replication stress, induce chromosomal instability, and lead to transcriptional reprograming, potentially generating context-specific therapeutic vulnerabilities. In this review, we examine the multifaceted biology of RB and evaluate how its loss influences responses to chemotherapy and targeted therapies. We highlight emerging strategies that exploit RB-deficient states using rational monotherapy and combination approaches. Reframing RB dysfunction from a binary biomarker to a driver of exploitable cellular vulnerabilities may inform and expand precision oncology strategies for aggressive and treatment-resistant cancers.