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ATR inhibition induces synthetic lethality in mismatch repair-deficient cells and augments immunotherapy
Mingchao Wang1,2, Xiaojuan Ran1,3, Wendy Leung1
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
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.
Insights
ATR inhibition selectively kills mismatch repair-deficient (MMR-d) cancer cells by inducing synthetic lethality. This approach enhances immunotherapy effectiveness and offers a promising strategy for MMR-d tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Immunology
Background:
- Mismatch repair (MMR) deficiency in cancer drives mutagenesis and serves as an immunotherapy biomarker.
- Many MMR-deficient (MMR-d) tumors exhibit resistance to current immunotherapies, necessitating novel therapeutic strategies.
- Targeting MMR-d cancer cells remains a critical challenge in oncology.
Purpose of the Study:
- To investigate the efficacy of ATR kinase inhibition in targeting MMR-d cancer cells.
- To elucidate the mechanisms underlying ATR inhibitor (ATRi)-induced synthetic lethality in MMR-d cells.
- To evaluate ATRi as a strategy to enhance immunotherapy for MMR-d tumors.
Main Methods:
- Utilized cell-based assays to assess the impact of ATR inhibition on MMR-d cancer cells.
- Investigated DNA damage induction, localization (colocalization with MSH2 and PCNA), and replication dependency.
- Employed syngeneic mouse models to evaluate in vivo tumor growth reduction and immune responses.
- Assessed cytoplasmic DNA fragment accumulation and cGAS-mediated interferon response.
- Combined ATRi with anti-PD-1 therapy in preclinical models.
Main Results:
- ATR inhibition preferentially killed MMR-d cancer cells through synthetic lethality.
- ATRi induced replication-dependent DNA damage, dependent on MUS81 nuclease.
- DNA damage colocalized with MSH2 and PCNA, indicating replication-associated structures.
- ATRi treatment reduced MMR-d tumor growth in mouse models, with partial mediation by CD8+ T cells.
- ATRi treatment led to cytoplasmic accumulation of nascent DNA fragments, activating interferon response.
- Combination of ATRi and anti-PD-1 demonstrated superior tumor growth inhibition compared to monotherapy.
Conclusions:
- ATR inhibition represents a targeted approach to selectively eliminate MMR-d cancer cells via synthetic lethality.
- ATRi enhances antitumor immunity by promoting interferon responses and sensitizing tumors to checkpoint blockade.
- The combination of ATRi and immunotherapy offers a promising therapeutic strategy for MMR-d tumors resistant to current treatments.
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