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

Anish Thomas*, Nobuyuki Takahashi, Vinodh N. Rajapakse, Xiaohu Zhang, Yilun Sun, Michele Ceribelli, Kelli M. Wilson, Yang Zhang, Erin Beck, Linda Sciuto, Samantha Nichols, Brian Elenbaas, Janusz Puc, Heike Dahmen, Astrid Zimmermann, Jillian Varonin, Christopher W. Schultz, Sehyun Kim, Hirity Shimellis, Parth DesaiCarleen Klumpp-Thomas, Lu Chen, Jameson Travers, Crystal McKnight, Sam Michael, Zina Itkin, Sunmin Lee, Akira Yuno, Min Jung Lee, Christophe E. Redon, Jessica D. Kindrick, Cody J. Peer, Jun S. Wei, Mirit I. Aladjem, William Douglas Figg, Seth M. Steinberg, Jane B. Trepel, Frank T. Zenke, Yves Pommier, Javed Khan, Craig J. Thomas

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

103 Scopus citations

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.

Original languageEnglish
Pages (from-to)566-579.e7
JournalCancer Cell
Volume39
Issue number4
DOIs
StatePublished - 12 Apr 2021
Externally publishedYes

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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