ATR Inhibition Is a Promising Radiosensitizing Strategy for Triple-Negative Breast Cancer.

Abstract

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 G2-M checkpoint, delayed resolution of DNA double-strand breaks, and reduced colony formation after radiotherapy in TNBC cells relative to normal-like breast epithelial cells. In vivo, VX-970 did not exhibit significant single-agent activity at the dose administered even in the context of genomic alterations predictive of ATR inhibitor responsiveness, but significantly sensitized TNBC PDXs to radiotherapy. Exome sequencing and functional testing demonstrated that combination therapy was effective in both HR-proficient and -deficient models. PDXs established from patients with chemoresistant TNBC were also highly radiosensitized. In conclusion, VX-970 is a tumor-specific radiosensitizer for TNBC. Patients with residual TNBC after neoadjuvant chemotherapy, a subset at particularly high risk of relapse, may be ideally suited for this treatment intensification strategy. Mol Cancer Ther; 17(11); 2462-72. ©2018 AACR.

• Authors: Xinyi Tu, Mohamed M Kahila, Qin Zhou, Jia Yu, Krishna R Kalari, Liewei Wang, William S Harmsen, Jian Yuan, Judy C Boughey, Matthew P Goetz, Jann N Sarkaria, Zhenkun Lou, Robert W Mutter
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 17 Issue 11 Pg. 2462-2472 (11 2018) ISSN: 1538-8514 [Electronic] United States
• PMID: 30166399 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Isoxazoles
• Pyrazines
• Radiation-Sensitizing Agents
• ATR protein, human
• Ataxia Telangiectasia Mutated Proteins
• CHEK1 protein, human
• Checkpoint Kinase 1
• CDC25A protein, human
• cdc25 Phosphatases
• berzosertib

Topics

• Animals
• Ataxia Telangiectasia Mutated Proteins (antagonists & inhibitors, metabolism)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Checkpoint Kinase 1 (metabolism)
• DNA Breaks, Double-Stranded (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Female
• Homologous Recombination (drug effects)
• Humans
• Isoxazoles (pharmacology, therapeutic use)
• Mice, Inbred NOD
• Mice, SCID
• Phosphorylation (drug effects)
• Proteolysis (drug effects)
• Pyrazines (pharmacology, therapeutic use)
• Radiation-Sensitizing Agents (pharmacology, therapeutic use)
• Triple Negative Breast Neoplasms (drug therapy, pathology, radiotherapy)
• Xenograft Model Antitumor Assays
• cdc25 Phosphatases (metabolism)