Targeting the Vulnerability of RB Tumor Suppressor Loss in Triple-Negative Breast Cancer

Abstract

Summary: Approximately 30% of triple-negative breast cancers (TNBCs) exhibit functional loss of the RB tumor suppressor, suggesting a target for precision intervention. Here, we use drug screens to identify agents specifically antagonized by the retinoblastoma tumor suppressor (RB) using CDK4/6 inhibitors. A number of candidate RB-synthetic lethal small molecules were identified, including anti-helmenthics, chemotherapeutic agents, and small-molecule inhibitors targeting DNA-damage checkpoints (e.g., CHK) and chromosome segregation (e.g., PLK1). Counter-screens using isogenic TNBC tumor cell lines and cell panels with varying endogenous RB statuses confirmed that therapeutic effects were robust and selective for RB loss of function. By analyzing TNBC clinical specimens, RB-deficient tumors were found to express high levels of CHK1 and PLK1. Loss of RB specifically resulted in loss of checkpoint functions governing DNA replication, yielding increased drug sensitivity. Xenograft models demonstrated RB-selective efficacy of CHK inhibitors. This study supports the possibility of selectively targeting RB loss in the treatment of TNBC. : Witkiewicz et al. demonstrate that the activation state of the RB tumor suppressor is a critical determinant for selected targeted therapies in models of TNBC. Loss of RB yields a selective vulnerability to replication and chromosome segregation stress. Drugs targeting CHK and PLK have increased efficacy in RB-deficient tumors. Keywords: RB, CDK4, palbociclib, E2F, cyclin, CHK1, PLK1, chemotherapy, retinoblastoma, ribociclib