ATR inhibition activates cancer cell cGAS/STING-interferon signaling and promotes antitumor immunity in small-cell lung cancer Journal Article
| Authors: | Taniguchi, H.; Chakraborty, S.; Takahashi, N.; Banerjee, A.; Caeser, R.; Zhan, Y. A.; Tischfield, S. E.; Chow, A.; Nguyen, E. M.; Villalonga, Á Q.; Manoj, P.; Shah, N. S.; Rosario, S.; Hayatt, O.; Qu, R.; de Stanchina, E.; Chan, J.; Mukae, H.; Thomas, A.; Rudin, C. M.; Sen, T. |
| Article Title: | ATR inhibition activates cancer cell cGAS/STING-interferon signaling and promotes antitumor immunity in small-cell lung cancer |
| Abstract: | Patients with small-cell lung cancer (SCLC) have poor prognosis and typically experience only transient benefits from combined immune checkpoint blockade (ICB) and chemotherapy. Here, we show that inhibition of ataxia telangiectasia and rad3 related (ATR), the primary replication stress response activator, induces DNA damage–mediated micronuclei formation in SCLC models. ATR inhibition in SCLC activates the stimulator of interferon genes (STING)–mediated interferon signaling, recruits T cells, and augments the antitumor immune response of programmed death-ligand 1 (PD-L1) blockade in mouse models. We demonstrate that combined ATR and PD-L1 inhibition causes improved antitumor response than PD-L1 alone as the second-line treatment in SCLC. This study shows that targeting ATR up-regulates major histocompatibility class I expression in preclinical models and SCLC clinical samples collected from a first-in-class clinical trial of ATR inhibitor, berzosertib, with topotecan in patients with relapsed SCLC. Targeting ATR represents a transformative vulnerability of SCLC and is a complementary strategy to induce STING-interferon signaling–mediated immunogenicity in SCLC. © 2024 The Authors |
| Keywords: | signal transduction; genetics; interferon; chemotherapy; topotecan; mouse; animal; metabolism; animals; mice; pyrazines; lung neoplasms; membrane proteins; lung cancer; drug effect; pathology; cell line, tumor; lung tumor; immunology; immune response; membrane protein; tumor cell line; atm protein; drug therapy; atr protein, human; pyrazine derivative; biological organs; cancer cells; small-cell lung cancer; small cell lung cancer; small cell lung carcinoma; ataxia telangiectasia; isoxazoles; isoxazole derivative; programmed death 1 ligand 1; nucleotidyltransferase; t-cells; antitumor immunity; cell signaling; nucleotidyltransferases; dna damages; immune checkpoint inhibitor; interferons; cancer models; humans; human; ataxia telangiectasia mutated proteins; immune checkpoint inhibitors; cd274 protein, human; b7-h1 antigen; anti-tumor immune; sting1 protein, human; cgas protein, human; berzosertib; mediated interferons; stresses response |
| Journal Title: | Science Advances |
| Volume: | 10 |
| Issue: | 39 |
| ISSN: | 2375-2548 |
| Publisher: | Amer Assoc Advancement Science |
| Date Published: | 2024-09-27 |
| Start Page: | eado4618 |
| Language: | English |
| DOI: | 10.1126/sciadv.ado4618 |
| PUBMED: | 39331709 |
| PROVIDER: | scopus |
| PMCID: | PMC11430494 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF. Corresponding MSK author is Triparna Sen -- Source: Scopus |
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