Translating RB1 predictive value in clinical cancer therapy: Are we there yet?

The retinoblastoma RB1 gene has been identified in the 80s as the first tumor suppressor. RB1 loss of function, as well alterations in its pathway, occur in most human cancers and often have prognostic value. RB1 has a key role in restraining cell cycle entry and, along with its family members, regulates a myriad of cellular processes and affects cell response to a variety of stimuli, ultimately determining cell fate. Consistently, RB1 status is a crucial determinant of the cell response to antitumoral therapies, impacting on the outcome of both traditional and modern anti-cancer strategies, including precision medicine approaches, such as kinase inhibitors, and immunotherapy. Despite many efforts however, the predictive value of RB1 status in the clinical practice is still underused, mainly owing to the complexity of RB1 function, to differences depending on the cellular context and on the therapeutic strategies, and, not-lastly, to technical issues. Here, we provide an overview of studies analyzing the role of RB1 in response to conventional cytotoxic and cytostatic therapeutic agents in different cancer types, including hormone dependent ones. We also review RB1 predictive value in the response to the last generation CDK4/6 inhibitors, other kinase inhibitors, and immunotherapy and discuss new emerging non-canonical roles of RB1 that could impact on the response to antitumoral treatments.