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

Molecular Cancer Therapeutics
Xinyi TuRobert W Mutter

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...Continue Reading

References

Oct 29, 2004·Nature Reviews. Cancer·Nicholas TurnerAlan Ashworth
Apr 5, 2007·Nature Protocols·Nicolaas A P FrankenChris van Bree
Feb 12, 2008·Nature·Stacey L EdwardsAlan Ashworth
Feb 21, 2008·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Marianne KyndiUNKNOWN Danish Breast Cancer Cooperative Group
Mar 8, 2008·Science·Thanos D HalazonetisJiri Bartek
Apr 17, 2008·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Paul L NguyenJay R Harris
Apr 17, 2008·Cancer Research·Elizabeth M SwisherToshiyasu Taniguchi
Jul 3, 2008·Nature Reviews. Molecular Cell Biology·Karlene A Cimprich, David Cortez
Aug 31, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Monika GraeserNicholas C Turner
Oct 23, 2010·Molecular Cell·Alberto Ciccia, Stephen J Elledge
Apr 15, 2011·Nature Chemical Biology·Philip M ReaperJohn R Pollard
May 10, 2011·Nature Structural & Molecular Biology·Luis I ToledoOscar Fernandez-Capetillo
Jun 3, 2011·The Journal of Clinical Investigation·Brian D LehmannJennifer A Pietenpol
Dec 3, 2011·The Journal of Clinical Investigation·David W SchoppyEric J Brown
Apr 18, 2012·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Gunter von MinckwitzSibylle Loibl
Sep 25, 2012·Nature·UNKNOWN Cancer Genome Atlas Network
Nov 9, 2012·International Journal of Cancer. Journal International Du Cancer·Amanda Capes-DavisLiz Kerrigan
Feb 8, 2013·Nature·Michael B BurnsReuben S Harris
Mar 15, 2013·The Journal of Biological Chemistry·Lin FengJunjie Chen
Dec 12, 2013·Nature Reviews. Molecular Cell Biology·Stephanie Panier, Simon J Boulton
Mar 3, 2015·Proceedings of the National Academy of Sciences of the United States of America·David W CesconTak W Mak
Jul 23, 2015·The New England Journal of Medicine·Timothy J WhelanUNKNOWN MA.20 Study Investigators
Jul 23, 2015·The New England Journal of Medicine·Philip M PoortmansUNKNOWN EORTC Radiation Oncology and Breast Cancer Groups
Aug 22, 2015·Biomolecules·Jan Benada, Libor Macurek
Nov 26, 2015·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Lise Bech Jellesmark ThorsenJens Overgaard
Jan 19, 2016·Nature Reviews. Cancer·Christopher J Lord, Alan Ashworth
Apr 14, 2016·Molecular Cell·Sergio RuizOscar Fernandez-Capetillo
May 3, 2016·Nature·Serena Nik-ZainalMichael R Stratton
Sep 30, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Elizabeth H StoverElizabeth M Swisher
Dec 16, 2016·PloS One·Eriko TokunagaYoshihiko Maehara
Jan 15, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Anosheh AfghahiMelinda L Telli
Jan 21, 2017·Nature Reviews. Cancer·Annette T ByrneLivio Trusolino
Apr 28, 2017·Cancers·Stuart RundleNicola J Curtin
Jun 1, 2017·The New England Journal of Medicine·Norikazu MasudaMasakazu Toi

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Citations

Jun 9, 2020·Expert Reviews in Molecular Medicine·Hannah L SmithNicola J Curtin
Jul 9, 2020·Cancer Science·Yunlong Hu, Mingzhou Guo
Jan 13, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Harshini MallipeddiRavi P Sahu
Feb 9, 2021·Biochimica Et Biophysica Acta. Reviews on Cancer·Juan JinXichun Hu
Feb 7, 2021·International Journal of Molecular Sciences·Rüveyda DokSandra Nuyts
Mar 12, 2021·Nucleic Acids Research·Ming GaoZhenkun Lou
Apr 21, 2021·International Journal of Radiation Biology·Sissel HaugeRandi G Syljuåsen
Jul 13, 2021·JCO Precision Oncology·Andrea M PeschCorey W Speers
Jul 21, 2021·International Journal of Radiation Biology·Jac A NickoloffRobert Hromas

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