2. Academic Validation
  3. Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress

Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress

  • Cancer Cell. 2021 Apr 12;39(4):566-579.e7. doi: 10.1016/j.ccell.2021.02.014.
Anish Thomas 1,  Nobuyuki Takahashi 2,  Vinodh N Rajapakse 2,  Xiaohu Zhang 3,  Yilun Sun 2,  Michele Ceribelli 3,  Kelli M Wilson 3,  Yang Zhang 2,  Erin Beck 3,  Linda Sciuto 2,  Samantha Nichols 2,  Brian Elenbaas 4,  Janusz Puc 4,  Heike Dahmen 5,  Astrid Zimmermann 5,  Jillian Varonin 6,  Christopher W Schultz 2,  Sehyun Kim 2,  Hirity Shimellis 2,  Parth Desai 2,  Carleen Klumpp-Thomas 3,  Lu Chen 3,  Jameson Travers 3,  Crystal McKnight 3,  Sam Michael 3,  Zina Itkin 3,  Sunmin Lee 2,  Akira Yuno 2,  Min-Jung Lee 2,  Christophe E Redon 2,  Jessica D Kindrick 7,  Cody J Peer 7,  Jun S Wei 8,  Mirit I Aladjem 2,  William Douglas Figg 7,  Seth M Steinberg 9,  Jane B Trepel 2,  Frank T Zenke 5,  Yves Pommier 2,  Javed Khan 8,  Craig J Thomas 10
Affiliations

Affiliations

  • 1 Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: anish.thomas@nih.gov.
  • 2 Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 3 Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institute of Health, Rockville, MD 20850, USA.
  • 4 EMD Serono Research and Development Institute Inc., Biopharma R&D, Translational Innovation Platform Oncology, Billerica, MA 01821, USA; A business of Merck KGaA, Darmstadt, Germany.
  • 5 Merck KGaA, Biopharma R&D, Translational Innovation Platform Oncology, Frankfurter Street 250, 64293 Darmstadt, Germany.
  • 6 Technology Transfer Center, National Cancer Institute, 9609 Medical Center Dr, Rockville, MD 20850, USA.
  • 7 Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 8 Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 9 Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 10 Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institute of Health, Rockville, MD 20850, USA; Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
PMID: 33848478 DOI: 10.1016/j.ccell.2021.02.014
Abstract

Small cell neuroendocrine cancers (SCNCs) are recalcitrant cancers arising from diverse primary sites that lack effective treatments. Using chemical genetic screens, we identified inhibition of ataxia telangiectasia and rad3 related (ATR), the primary activator of the replication stress response, and Topoisomerase I (TOP1), nuclear Enzyme that suppresses genomic instability, as synergistically cytotoxic in small cell lung Cancer (SCLC). In a proof-of-concept study, we combined M6620 (berzosertib), first-in-class ATR Inhibitor, and TOP1 inhibitor topotecan in patients with relapsed SCNCs. Objective response rate among patients with SCLC was 36% (9/25), achieving the primary efficacy endpoint. Durable tumor regressions were observed in patients with platinum-resistant SCNCs, typically fatal within weeks of recurrence. SCNCs with high neuroendocrine differentiation, characterized by enhanced replication stress, were more likely to respond. These findings highlight replication stress as a potentially transformative vulnerability of SCNCs, paving the way for rational patient selection in these cancers, now treated as a single disease.

Keywords

DNA damage response; DNA topoisomerases; SCLC; ataxia telangiectasia mutated and rad3 related; cell-cycle checkpoints; replication stress; small cell neuroendocrine cancers; translational research.

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