ATR inhibition induces synthetic lethality in mismatch repair-deficient cells and augments immunotherapy.
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2023-10
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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.
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Wang, Mingchao, Xiaojuan Ran, Wendy Leung, Ajinkya Kawale, Sneha Saxena, Jian Ouyang, Parasvi S Patel, Yuting Dong, et al. (2023). ATR inhibition induces synthetic lethality in mismatch repair-deficient cells and augments immunotherapy. Genes & development, 37(19-20). pp. 929–943. 10.1101/gad.351084.123 Retrieved from https://hdl.handle.net/10161/33650.
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Scholars@Duke
Li Lan
The Lan Lab is dedicated to researching how cancer cells respond to DNA damage through DNA repair mechanisms and developing innovative strategies to target these pathways in cancer therapy. Our significant contributions include uncovering the critical role of PARP in DNA repair, leading to successful applications of PARP inhibitors in the treatment of breast, ovarian, and other types of cancer. We study how DNA responds to oxidative damage at specific chromosomal locations, significantly advancing our understanding of DNA damage response in different chromosomal environments. Furthermore, our recent investigations have revealed a novel mRNA and R-loop-dependent DNA repair pathway that acts as a protective mechanism for the transcribed regions of the genome, introducing a new paradigm in the field of DNA repair research.
Some of the research interests of the Lan Lab:
- Unraveling the underlying mechanisms of mRNA and R-loop-dependent DNA repair (RDDR) in cancer and developing targeted therapies. We actively investigate the molecular mechanisms of the RDDR pathway, including its regulators. We study how the pathway is processed coupling with DNA replication and chromatin remodeling. We employ screening platforms to monitor the RDDR pathway and the function of RDDR proteins, with the goal of developing inhibitors that disrupt RDDR in cancer cells. We try to identify RDDR biomarkers for patient stratification and predict the response to RDDR-targeted therapy. Additionally, we explore its potential applications in gene editing. Our research spans from basic science to translation, with a focus on the potential of mRNA-modifying enzymes as therapeutic targets for treating cancers exhibiting increased genome instability.
- Investigating the response of telomeres to oxidative damage in cancer and exploiting vulnerabilities in cancer cells. By comprehending how cancer cells respond to oxidative damage at telomeres through mechanisms such as telomerase, alternative lengthening of telomeres, and mRNA and R-loop-mediated repair pathways, our goal is to selectively eliminate cancer cells experiencing oxidative stress.
- Exploring the interplay between DNA damage response and immune response in cancer. Our investigations have shed light on the role of the DNA sensor cGAS in triggering the STING-dependent interferon response, subsequently modulating the tumor microenvironment to enhance anti-tumor immunity. Currently, we are examining how DNA damage and R-loops regulate the functions of cGAS in cancer cells. Through our mechanistic studies, we aim to provide a molecular basis for enhancing immune checkpoint blockade-mediated therapy by modulating specific cGAS functions in combination with RDDR targeted therapy.
Overall, the research conducted by the Lan Lab strives to advance our understanding of DNA repair processes in cancer and the role of RNA and R-loops in these processes. We are dedicated to translating our findings into innovative therapeutic strategies that have the potential to revolutionize cancer treatment and improve patient outcomes.
Xiao-Fan Wang
The current research in the Wang laboratory mainly focuses on the elucidation of molecular nature and signaling mechanisms associated with the initiation of cellular senescence. In addition, we continue to study changes in tumor microenvironment that promotes tumor progression and metastasis, particularly how tumor cells interact with the immune system. Ultimately, we hope that our studies in these areas to lead to the development of novel therapeutics for the treatment of various types of human cancer.
Lee Zou
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