ATR inhibition activates cancer cell cGAS/STING-interferon signaling and promotes antitumor immunity in small-cell lung cancer
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.
Authors
- Nobuyuki Takahashi (ORCID: https://orcid.org/0000-0002-8592-6528)
- Elisa de Stanchina (ORCID: https://orcid.org/0000-0002-3873-315X)
- Nisargbhai Shah (ORCID: https://orcid.org/0000-0002-0214-4919)
- Joseph M. Chan (ORCID: https://orcid.org/0000-0001-5249-7395)
- Àlvaro Quintanal-Villalonga (ORCID: https://orcid.org/0000-0002-7234-3446)
- Hirokazu Taniguchi (ORCID: https://orcid.org/0000-0003-2414-8344)
- Triparna Sen (ORCID: https://orcid.org/0000-0003-4673-7481)
- Omar Hayatt (ORCID: https://orcid.org/0009-0007-7453-5621)
- Charles M. Rudin (ORCID: https://orcid.org/0000-0001-5204-3465)
- Parvathy Manoj (ORCID: https://orcid.org/0000-0002-1121-0121)
- Avisek Banerjee (ORCID: https://orcid.org/0000-0001-5697-6721)
- Andrew Chow (ORCID: https://orcid.org/0000-0003-1151-2450)
- Rui Qu (ORCID: https://orcid.org/0009-0009-1185-9076)
- Hiroshi Mukae (ORCID: https://orcid.org/0000-0002-1429-5706)
- Anish Thomas (ORCID: https://orcid.org/0000-0003-3293-3115)
- Rebecca Caeser (ORCID: https://orcid.org/0000-0002-8416-9844)
- Sam E. Tischfield
- Yingqian A. Zhan (ORCID: https://orcid.org/0000-0002-3548-9227)
- Evelyn M. Nguyen (ORCID: https://orcid.org/0000-0002-0809-1870)
- Subhamoy Chakraborty (ORCID: https://orcid.org/0000-0003-0626-9011)
- S. Rivera Rosario
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Cornell University (US)
- Parker Institute for Cancer Immunotherapy (US)
- National Cancer Institute (US)
- National Cancer Center Hospital East (JP)
- Center for Cancer Research (US)
- Molecular Oncology (United States) (US)
- Nagasaki University (JP)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Science Advances
- Published
- 2024-09-27
- DOI
- https://doi.org/10.1126/sciadv.ado4618
- Citations
- 37
- Primary Topic
- Lung Cancer Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 10.45