ArticleCancer cell2021
Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress.
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Article in Cancer cell, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 126 papers, 1 of them a synthesis that pooled it.
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126citing papers in PubMed, 1 pooled it
12.9field-weighted citation impact, top 1% of its field
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
126 citing papers in PubMed, 1 synthesis or guideline pooled it, 176 citations in OpenAlex.
- Efficacy and toxicity of lurbinectedin in subsequent systemic therapy of extensive-stage small cell lung cancer: a meta-analysis.BMC cancer · 2024Pooled it
- Trial
- NCI 10211: a phase II, single-arm study of berzosertib in combination with irinotecan in patients with advanced TP53 mutant gastroesophageal cancer.The oncologist · 2025Trial
- A Phase II Pilot Study of Anti-PD-L1, Durvalumab, and a PARP Inhibitor, Olaparib in Patients With Metastatic Triple-Negative Breast Cancer With or Without Germline BRCA Mutation.Cancer medicine · 2025Trial
- Trial
- Plasma nucleosome profiling reports on tumor burden and molecular subtypes in small cell lung cancer.The Journal of clinical investigation · 2026Article
- Replication stress in cancer: origins, consequences and therapeutic opportunities.Nature reviews. Cancer · 2026Review
- ATR inhibition induces NF-κB-dependent immunogenicity in Merkel cell carcinoma independent of cGAS-STING.NPJ precision oncology · 2026Article
- Spindle Assembly Checkpoint Competency Determines Sensitivity to KIF18A Inhibition in Small Cell Lung Cancer.Cancer research communications · 2026Article
- Review
- Blockade of Tumor-Intrinsic TGFβ Signaling Drives Hyperprogression in Small Cell Lung Cancer.Cancer discovery · 2026Article
- ABL kinase inactivation induces transcription-replication conflicts and impairs replication fork progression in metastatic small cell lung cancer.Cell reports · 2026Article
- Loss of the USP22 deubiquitylase confers resistance to chemotherapy in small cell lung cancer.Nature communications · 2026Article
- Automated detection and characterization of small cell lung cancer liver metastasis on computed tomography.Diagnostic and interventional radiology (Ankara, Turkey) · 2026Article
- Topoisomerase I inhibitor antibody-drug conjugates in breast cancer: the relevance of the DNA damage response to resistance, response, and combination treatment strategies.Breast cancer research and treatment · 2026Review
- Berzosertib enhances the sensitivity of pediatric diffuse midline glioma H3K27-altered cells to radiotherapy.Cell death & disease · 2026Article
- ATM functions as a rheostat of metabolic stress in small-cell lung cancer.bioRxiv : the preprint server for biology · 2026Article
- Targeting DNA Topoisomerase I for the Treatment of Cancer: Past, Present and Future.Journal of molecular biology · 2026Review
- BET inhibitor-based combinations targeting novel dependencies in MECOM-rearranged (r) AML.Leukemia · 2026Article
- Novel therapeutic potential of the PARP inhibitor talazoparib in synovial sarcoma and its combined effect with ATR inhibitor.Discover oncology · 2026Article
66 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
41 authors at 4 institutions in 2 countries.
Anish ThomasDevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: anish.thomas@nih.gov.
Nobuyuki TakahashiDevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Vinodh N RajapakseDevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Xiaohu ZhangDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institute of Health, Rockville, MD 20850, USA.
Yilun SunDevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Michele CeribelliDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institute of Health, Rockville, MD 20850, USA.
Kelli M WilsonDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institute of Health, Rockville, MD 20850, USA.
Yang ZhangDevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Erin BeckDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institute of Health, Rockville, MD 20850, USA.
Linda SciutoDevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Samantha NicholsDevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Brian ElenbaasEMD Serono Research and Development Institute Inc., Biopharma R&D, Translational Innovation Platform Oncology, Billerica, MA 01821, USA; A business of Merck KGaA, Darmstadt, Germany.
Janusz PucEMD Serono Research and Development Institute Inc., Biopharma R&D, Translational Innovation Platform Oncology, Billerica, MA 01821, USA; A business of Merck KGaA, Darmstadt, Germany.
Heike DahmenMerck KGaA, Biopharma R&D, Translational Innovation Platform Oncology, Frankfurter Street 250, 64293 Darmstadt, Germany.
Astrid ZimmermannMerck KGaA, Biopharma R&D, Translational Innovation Platform Oncology, Frankfurter Street 250, 64293 Darmstadt, Germany.
Jillian VaroninTechnology Transfer Center, National Cancer Institute, 9609 Medical Center Dr, Rockville, MD 20850, USA.
Christopher W SchultzDevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Sehyun KimDevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Hirity ShimellisDevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Parth DesaiDevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Carleen Klumpp-ThomasDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institute of Health, Rockville, MD 20850, USA.
Lu ChenDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institute of Health, Rockville, MD 20850, USA.
Jameson TraversDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institute of Health, Rockville, MD 20850, USA.
Crystal McKnightDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institute of Health, Rockville, MD 20850, USA.
Sam MichaelDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institute of Health, Rockville, MD 20850, USA.
Zina ItkinDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institute of Health, Rockville, MD 20850, USA.
Sunmin LeeDevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Akira YunoDevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Min-Jung LeeDevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Christophe E RedonDevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Jessica D KindrickClinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Cody J PeerClinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Jun S WeiGenetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Mirit I AladjemDevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
William Douglas FiggClinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Seth M SteinbergBiostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Jane B TrepelDevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Frank T ZenkeMerck KGaA, Biopharma R&D, Translational Innovation Platform Oncology, Frankfurter Street 250, 64293 Darmstadt, Germany.
Yves PommierDevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Javed KhanGenetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Craig J ThomasDivision 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.
National Institutes of Health · USNational Center for Advancing Translational Sciences · USMerck (Germany) · DEOffice of Technology Transfer · US
Funding
Research Services Section (RSS)ZICTR000242 · NCATS · NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES · PI WILSON, KELLI · 2015 to 2025
$64.9MInitiation of DNA Replication in Mammalian CellsZIABC010411 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI ALADJEM, MIRIT · 2009 to 2025
$25.0MDNA Repair, Cell Cycle Checkpoints and Apoptosis as Targets for Anticancer DrugsZIABC006150 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI POMMIER, YVES · 2009 to 2025
$23.0MExploiting DNA Replicative Stress for Novel Small Cell Lung Cancer TherapiesZIABC011793 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI THOMAS, ANISH · 2018 to 2025
$16.4MOffice of Collaborative BiostatisticsZIDSC007202 · NCI · DIVISION OF CLINICAL SCIENCES - NCI · PI CHOO-WOSOBA, HYOYOUNG · 2009 to 2025
$14.5MUsing Clinical Pharmacology Principles to Develop New Anticancer TherapiesZICSC006537 · NCI · DIVISION OF CLINICAL SCIENCES - NCI · PI FIGG, WILLIAM DOUGLAS · 2009 to 2025
$14.4MSignal Transduction Events and the Regulation of Cell GrowthZICSC006743 · NCI · DIVISION OF CLINICAL SCIENCES - NCI · PI TREPEL, JANE B · 2009 to 2023
$13.8MBIOINFORMATICS: SYSTEMS BIOLOGY OF PEDIATRIC CANCERSZIABC011002 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI KHAN, JAVED · 2009 to 2025
$9.3MHTS enabled examination of drug combinationsZIATR000047 · NCATS · NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES · PI THOMAS, CRAIG · 2015 to 2025
$7.1MDevelopment Therapeutics Branch Clinical TrialsZIABC011746 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI POMMIER, YVES · 2017 to 2025
$2.6MIntramural NIH HHS ZIA BC011793
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.
Indexed as
AgedAntineoplastic AgentsAtaxia Telangiectasia Mutated ProteinsDNA ReplicationDNA Topoisomerases, Type IGenomic InstabilityHumansIsoxazolesLung NeoplasmsMiddle AgedNeoplasm Recurrence, LocalProtein Kinase InhibitorsPyrazinesSignal TransductionSmall Cell Lung CarcinomaAntineoplastic AgentsAtaxia Telangiectasia Mutated ProteinsATR protein, humanberzosertibDNA Topoisomerases, Type IIsoxazolesProtein Kinase InhibitorsPyrazinesataxia telangiectasia mutated and rad3 relatedcell-cycle checkpointsDNA damage responseDNA topoisomerasesreplication stressSCLCsmall cell neuroendocrine cancerstranslational research
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