RB loss sensitizes triple-negative breast cancer to apoptosis induced by cellular stress

Abstract Functional loss of RB1 is a common genetic alteration in triple-negative breast cancer (TNBC) and is associated with poor response to targeted therapies, including CDK4/6 inhibitors. In this study, we perform an unbiased drug screen and identify that co-targeting distinct cell cycle processes such as DNA repair and mitosis induce synthetic lethality selectively in RB-deficient models. While RB loss promotes replication stress and mitotic dysregulation, the selective lethality observed with these combinations arises from an alternate mechanism. Under RB-deficient conditions, cells undergo rapid apoptosis in response to cellular stress induced by cell cycle inhibition. This pro-apoptotic response is further augmented by using a pharmacological agent, birinapant that targets XIAP, which is an endogenous inhibitor of the apoptotic pathway. Birinapant in combination with CHK1 or AURKA inhibitors results in selective cell killing in RB-deficient TNBC models and yields durable disease control via apoptosis in vivo. In conclusion, RB loss in TNBC displays an enhanced vulnerability to pro-apoptotic signaling that can enable the effective implementation of new targeted therapeutic strategies.