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ATR inhibition induces synthetic lethality in mismatch repair-deficient cells and augments immunotherapy.

Authors
  • Wang, Mingchao1, 2
  • Ran, Xiaojuan1, 3
  • Leung, Wendy1
  • Kawale, Ajinkya1
  • Saxena, Sneha1
  • Ouyang, Jian1, 3
  • Patel, Parasvi S1
  • Dong, Yuting1
  • Yin, Tao3
  • Shu, Jian2
  • Manguso, Robert T1, 4
  • Lan, Li1, 5
  • Wang, Xiao-Fan3
  • Lawrence, Michael S1, 4
  • Zou, Lee6, 3, 7
  • 1 Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
  • 2 Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
  • 3 Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina 27708, USA.
  • 4 Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA.
  • 5 Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
  • 6 Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA; [email protected].
  • 7 Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Type
Published Article
Journal
Genes & development
Publication Date
Oct 01, 2023
Volume
37
Issue
19-20
Pages
929–943
Identifiers
DOI: 10.1101/gad.351084.123
PMID: 37932012
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The mismatch repair (MMR) deficiency of cancer cells drives mutagenesis and offers a useful biomarker for immunotherapy. However, many MMR-deficient (MMR-d) tumors do not respond to immunotherapy, highlighting the need for alternative approaches to target MMR-d cancer cells. Here, we show that inhibition of the ATR kinase preferentially kills MMR-d cancer cells. Mechanistically, ATR inhibitor (ATRi) imposes synthetic lethality on MMR-d cells by inducing DNA damage in a replication- and MUS81 nuclease-dependent manner. The DNA damage induced by ATRi is colocalized with both MSH2 and PCNA, suggesting that it arises from DNA structures recognized by MMR proteins during replication. In syngeneic mouse models, ATRi effectively reduces the growth of MMR-d tumors. Interestingly, the antitumor effects of ATRi are partially due to CD8+ T cells. In MMR-d cells, ATRi stimulates the accumulation of nascent DNA fragments in the cytoplasm, activating the cGAS-mediated interferon response. The combination of ATRi and anti-PD-1 antibody reduces the growth of MMR-d tumors more efficiently than ATRi or anti-PD-1 alone, showing the ability of ATRi to augment the immunotherapy of MMR-d tumors. Thus, ATRi selectively targets MMR-d tumor cells by inducing synthetic lethality and enhancing antitumor immunity, providing a promising strategy to complement and augment MMR deficiency-guided immunotherapy. © 2023 Wang et al.; Published by Cold Spring Harbor Laboratory Press.

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