ArticleEMBO molecular medicine2019
Chlorambucil targets BRCA1/2-deficient tumours and counteracts PARP inhibitor resistance.
Article in EMBO molecular medicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT04692740 (A Pilot Study of Chlorambucil in Pre-treated Metastatic Pancreatic Adenocarcinoma Patients Bearing a Germ Line BRCA or Other DNA Defects Repair), which is not on this map. Cited by 25 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 Pilot Study of Chlorambucil in Pre-treated Metastatic Pancreatic Adenocarcinoma Patients Bearing a Germ Line BRCA or Other DNA Defects Repair (DDR) Mutations.
Who cites it
25 citing papers in PubMed, 36 citations in OpenAlex.
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- RAD51C-XRCC3 structure and cancer patient mutations define DNA replication roles.Nature communications · 2023Article
- Two-Step Validation Approach for Tools To Study the DNA Repair Enzyme SNM1A.Chembiochem : a European journal of chemical biology · 2023Article
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- Homologous Recombination Deficiency Scar: Mutations and Beyond-Implications for Precision Oncology.Cancers · 2022Review
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- Anti-tumoural activity of the G-quadruplex ligand pyridostatin against BRCA1/2-deficient tumours.EMBO molecular medicine · 2022Article
- Development and Validation of a Prognostic Classifier Based on Lipid Metabolism-Related Genes for Breast Cancer.Journal of inflammation research · 2022Article
- KMT2C is a potential biomarker of prognosis and chemotherapy sensitivity in breast cancer.Breast cancer research and treatment · 2021Article
- New Synthetic Analogs of Nitrogen Mustard DNA Interstrand Cross-Links and Their Use to Study Lesion Bypass by DNA Polymerases.Chemical research in toxicology · 2021Article
- Identification of Bioactive SNM1A Inhibitors.ACS omega · 2021Article
- Appended Aromatic Moieties in Flexible Bis-3-chloropiperidines Confer Tropism against Pancreatic Cancer Cells.ChemMedChem · 2021Article
- Aromatic Linkers Unleash the Antiproliferative Potential of 3-Chloropiperidines Against Pancreatic Cancer Cells.ChemMedChem · 2020Article
- Effect of sodium butyrate on ABC transporters in lung cancer A549 and colorectal cancer HCT116 cells.Oncology letters · 2020Article
- Article
Corrections and comments
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Authors and funding
24 authors at 4 institutions in 3 countries.
Funding
Abstract
Due to compromised homologous recombination (HR) repair, BRCA1- and BRCA2-mutated tumours accumulate DNA damage and genomic rearrangements conducive of tumour progression. To identify drugs that target specifically BRCA2-deficient cells, we screened a chemical library containing compounds in clinical use. The top hit was chlorambucil, a bifunctional alkylating agent used for the treatment of chronic lymphocytic leukaemia (CLL). We establish that chlorambucil is specifically toxic to BRCA1/2-deficient cells, including olaparib-resistant and cisplatin-resistant ones, suggesting the potential clinical use of chlorambucil against disease which has become resistant to these drugs. Additionally, chlorambucil eradicates BRCA2-deficient xenografts and inhibits growth of olaparib-resistant patient-derived tumour xenografts (PDTXs). We demonstrate that chlorambucil inflicts replication-associated DNA double-strand breaks (DSBs), similarly to cisplatin, and we identify ATR, FANCD2 and the SNM1A nuclease as determinants of sensitivity to both drugs. Importantly, chlorambucil is substantially less toxic to normal cells and tissues in vitro and in vivo relative to cisplatin. Because chlorambucil and cisplatin are equally effective inhibitors of BRCA2-compromised tumours, our results indicate that chlorambucil has a higher therapeutic index than cisplatin in targeting BRCA-deficient tumours.
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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.