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

Anish Thomas1, Nobuyuki Takahashi1, Vinodh N Rajapakse1

  • 1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Cancer Cell
|April 13, 2021
PubMed

Insights

Combining ATR and TOP1 inhibitors shows promise for treating small cell neuroendocrine cancers (SCNCs). This approach yielded significant responses in patients with relapsed SCLC, highlighting replication stress as a key vulnerability.

Area of Science:

  • Oncology
  • Cancer Biology
  • Pharmacology

Background:

  • Small cell neuroendocrine cancers (SCNCs) are aggressive and lack effective treatments.
  • Identifying novel therapeutic vulnerabilities is crucial for improving patient outcomes.

Purpose of the Study:

  • To investigate the synergistic cytotoxicity of inhibiting ataxia telangiectasia and rad3 related (ATR) and topoisomerase I (TOP1) in SCNC.
  • To evaluate the efficacy of combining an ATR inhibitor (berzosertib) with a TOP1 inhibitor (topotecan) in patients with relapsed SCNCs.

Main Methods:

  • Chemical genetic screens to identify synergistic drug targets.
  • A proof-of-concept clinical trial combining berzosertib and topotecan in relapsed SCNC patients.
  • Assessment of objective response rate (ORR) and tumor regression.

Main Results:

  • The combination therapy achieved an ORR of 36% (9/25) in small cell lung cancer (SCLC) patients.
  • Durable tumor regressions were observed in platinum-resistant SCNC patients.
  • SCNCs with high neuroendocrine differentiation and enhanced replication stress showed higher response rates.

Conclusions:

  • Inhibition of ATR and TOP1 is synergistically cytotoxic in SCLC.
  • Combination therapy with berzosertib and topotecan demonstrates efficacy in relapsed SCNCs.
  • Replication stress represents a targetable vulnerability in SCNCs, enabling rational patient selection.
Keywords:
DNA damage responseDNA topoisomerasesSCLCataxia telangiectasia mutated and rad3 relatedcell-cycle checkpointsreplication stresssmall cell neuroendocrine cancerstranslational research

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