Targeting the Vulnerability of RB Tumor Suppressor Loss in Triple-Negative Breast Cancer.
Abstract
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.
Collections
Subject
Cell Line, Tumor
Animals
Humans
Mice
Protein-Serine-Threonine Kinases
Cell Cycle Proteins
Retinoblastoma Protein
Proto-Oncogene Proteins
Antineoplastic Agents
Protein Kinase Inhibitors
Drug Screening Assays, Antitumor
Xenograft Model Antitumor Assays
Cell Proliferation
Female
Cell Cycle Checkpoints
Triple Negative Breast Neoplasms
Checkpoint Kinase 1
Research team
Gene Function
Language
eng
Date accepted
2018-01-08
License start date
2018-01
Citation
Cell reports, 2018, 22 (5), pp. 1185 - 1199
Publisher
CELL PRESS
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
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