ArticleCancer discovery2014
Synthetic lethality in ATM-deficient RAD50-mutant tumors underlies outlier response to cancer therapy.
Article in Cancer discovery, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02487095 (A Phase I/II Trial of Topotecan With VX-970), which is not on this map. Cited by 76 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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.
A Phase I/II Trial of Topotecan With VX-970 (M6620), an ATR Kinase Inhibitor in Small Cell Cancers
Who cites it
76 citing papers in PubMed, 121 citations in OpenAlex.
- Article
- Ataxia telangiectasia mutated (ATM) kinase as a predictive biomarker in clinical oncology: implications for a precision treatment approach.Neoplasia (New York, N.Y.) · 2026Review
- RAD50 missense variants differentially affect the DNA damage response and mitotic progression.FEBS letters · 2025Article
- Defects in the DNA Damage Response of Patient-derived Endometriosis Stromal Cells.bioRxiv : the preprint server for biology · 2025Article
- Mouse MRE11-RAD50-NBS1 is needed to start and extend meiotic DNA end resection.Nature communications · 2025Article
- Advances in DNA damage response inhibitors in colorectal cancer therapy.Acta biochimica et biophysica Sinica · 2024Review
- Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation.The Journal of clinical investigation · 2024Article
- Genomic and Transcriptomic Characteristics of Metastatic Thyroid Cancers with Exceptional Responses to Radioactive Iodine Therapy.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- Importance of Germline and Somatic Alterations in HumanInternational journal of molecular sciences · 2023Review
- Therapeutic Targeting of DNA Damage Repair in the Era of Precision Oncology and Immune Checkpoint Inhibitors.Journal of immunotherapy and precision oncology · 2023Review
- DNA Repair Mechanisms, Protein Interactions and Therapeutic Targeting of the MRN Complex.Cancers · 2022Review
- Cancer Cells Haploinsufficient for ATM Are Sensitized to PARP Inhibitors byInternational journal of molecular sciences · 2022Article
- Article
- Article
- Homologous Recombination Deficiency: Cancer Predispositions and Treatment Implications.The oncologist · 2021Review
- The dynamic nature of the Mre11-Rad50 DNA break repair complex.Progress in biophysics and molecular biology · 2021Review
- The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers.Scientific reports · 2021Article
- Article
- Article
- Inhibition of the ATM/Chk2 axis promotes cGAS/STING signaling in ARID1A-deficient tumors.The Journal of clinical investigation · 2020Article
16 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
24 authors at 2 institutions in 1 country.
Funding
Abstract
unlabelledMetastatic solid tumors are almost invariably fatal. Patients with disseminated small-cell cancers have a particularly unfavorable prognosis, with most succumbing to their disease within two years. Here, we report on the genetic and functional analysis of an outlier curative response of a patient with metastatic small-cell cancer to combined checkpoint kinase 1 (CHK1) inhibition and DNA-damaging chemotherapy. Whole-genome sequencing revealed a clonal hemizygous mutation in the Mre11 complex gene RAD50 that attenuated ATM signaling which in the context of CHK1 inhibition contributed, via synthetic lethality, to extreme sensitivity to irinotecan. As Mre11 mutations occur in a diversity of human tumors, the results suggest a tumor-specific combination therapy strategy in which checkpoint inhibition in combination with DNA-damaging chemotherapy is synthetically lethal in tumor cells but not normal cells with somatic mutations that impair Mre11 complex function. SIGNIFICANCE: Strategies to effect deep and lasting responses to cancer therapy in patients with metastatic disease have remained difficult to attain, especially in early-phase clinical trials. Here, we present an in-depth genomic and functional genetic analysis identifying RAD50 hypomorphism as a contributing factor to a curative response to systemic combination therapy in a patient with recurrent, metastatic small-cell cancer.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.