vx-970 and Triple-Negative-Breast-Neoplasms

Triple-negative breast cancer (TNBC) is characterized by elevated locoregional recurrence risk despite aggressive local therapies. New tumor-specific radiosensitizers are needed. We hypothesized that the ATR inhibitor, VX-970 (now known as M6620), would preferentially radiosensitize TNBC. Noncancerous breast epithelial and TNBC cell lines were investigated in clonogenic survival, cell cycle, and DNA damage signaling and repair assays. In addition, patient-derived xenograft (PDX) models generated prospectively as part of a neoadjuvant chemotherapy study from either baseline tumor biopsies or surgical specimens with chemoresistant residual disease were assessed for sensitivity to fractionated radiotherapy, VX-970, or the combination. To explore potential response biomarkers, exome sequencing was assessed for germline and/or somatic alterations in homologous recombination (HR) genes and other alterations associated with ATR inhibitor sensitivity. VX-970 preferentially inhibited ATR-Chk1-CDC25a signaling, abrogated the radiotherapy-induced G

Topics: Animals; Ataxia Telangiectasia Mutated Proteins; cdc25 Phosphatases; Cell Cycle Checkpoints; Cell Line, Tumor; Checkpoint Kinase 1; DNA Breaks, Double-Stranded; Drug Resistance, Neoplasm; Female; Homologous Recombination; Humans; Isoxazoles; Mice, Inbred NOD; Mice, SCID; Phosphorylation; Proteolysis; Pyrazines; Radiation-Sensitizing Agents; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays