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

Xinyi Tu, Mohamed M. Kahila, Qin Zhou, Jia Yu, Krishna R Kalari, Liewei M Wang, William S. Harmsen, Jian Yuan, Judy C Boughey, Matthew Philip Goetz, Jann N Sarkaria, Zhenkun Lou, Robert Mutter

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2462-2472
Number of pages11
JournalMolecular Cancer Therapeutics
Volume17
Issue number11
DOIs
StatePublished - Nov 1 2018

Fingerprint

Triple Negative Breast Neoplasms
Radiotherapy
Exome
Homologous Recombination
Neoplasms
Breast
Recurrence
Drug Therapy
Double-Stranded DNA Breaks
Heterografts
DNA Repair
DNA Damage
Cell Cycle
Therapeutics
Biomarkers
Epithelial Cells
VX-970
Biopsy
Cell Line
Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

ATR Inhibition Is a Promising Radiosensitizing Strategy for Triple-Negative Breast Cancer. / Tu, Xinyi; Kahila, Mohamed M.; Zhou, Qin; Yu, Jia; Kalari, Krishna R; Wang, Liewei M; Harmsen, William S.; Yuan, Jian; Boughey, Judy C; Goetz, Matthew Philip; Sarkaria, Jann N; Lou, Zhenkun; Mutter, Robert.

In: Molecular Cancer Therapeutics, Vol. 17, No. 11, 01.11.2018, p. 2462-2472.

Research output: Contribution to journalArticle

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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.",
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AU - Kalari, Krishna R

AU - Wang, Liewei M

AU - Harmsen, William S.

AU - Yuan, Jian

AU - Boughey, Judy C

AU - Goetz, Matthew Philip

AU - Sarkaria, Jann N

AU - Lou, Zhenkun

AU - Mutter, Robert

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