Targeting the Vulnerability of RB Tumor Suppressor Loss in Triple-Negative Breast Cancer.
MetadataShow full item record
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.
Version of record
Cell Line, Tumor
Cell Cycle Proteins
Protein Kinase Inhibitors
Drug Screening Assays, Antitumor
Xenograft Model Antitumor Assays
Cell Cycle Checkpoints
Triple Negative Breast Neoplasms
Checkpoint Kinase 1
License start date
Cell reports, 2018, 22 (5), pp. 1185 - 1199
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/
Showing items related by title, author, creator and subject.
Structural Basis for Auto-Inhibition of the NDR1 Kinase Domain by an Atypically Long Activation Segment. Xiong, S; Lorenzen, K; Couzens, AL; Templeton, CM; Rajendran, D; Mao, DYL; Juang, Y-C; Chiovitti, D; Kurinov, I; Guettler, S; Gingras, A-C; Sicheri, F (2018-08)The human NDR family kinases control diverse aspects of cell growth, and are regulated through phosphorylation and association with scaffolds such as MOB1. Here, we report the crystal structure of the human NDR1 kinase ...
Phosphorylation-mediated interactions with TOPBP1 couple 53BP1 and 9-1-1 to control the G1 DNA damage checkpoint. Bigot, N; Day, M; Baldock, RA; Watts, FZ; Oliver, AW; Pearl, LH (2019-05-28)Coordination of the cellular response to DNA damage is organised by multi-domain 'scaffold' proteins, including 53BP1 and TOPBP1, which recognise post-translational modifications such as phosphorylation, methylation and ...
Martino, F; Pal, M; Muñoz-Hernández, H; Rodríguez, CF; Núñez-Ramírez, R; Gil-Carton, D; Degliesposti, G; Skehel, JM; Roe, SM; Prodromou, C; Pearl, LH; Llorca, O (2018-04-16)The R2TP/Prefoldin-like co-chaperone, in concert with HSP90, facilitates assembly and cellular stability of RNA polymerase II, and complexes of PI3-kinase-like kinases such as mTOR. However, the mechanism by which this ...