ArticleJournal of experimental & clinical cancer research : CR2021
Vulnerability to low-dose combination of irinotecan and niraparib in ATM-mutated colorectal cancer.
Article in Journal of experimental & clinical cancer research : CR, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.
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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
17 citing papers in PubMed, 1 synthesis or guideline pooled it, 37 citations in OpenAlex.
- ATM is associated with the prognosis of colorectal cancer: a systematic review.Frontiers in oncology · 2025Pooled it
- TensoGraph: a tensor-transformer framework for global-local drug synergy prediction on heterogeneous graphs.Briefings in bioinformatics · 2026Article
- Maritoclax Overcomes FBW7 Deficiency-Driven Irinotecan Resistance in Colorectal Cancer by Targeting MCL1.Cancer medicine · 2025Article
- Navigating the Colorectal Cancer Maze: Unveiling Pathways To Diagnosis, Management, Pathophysiology and Prevention.Current oncology reports · 2025Review
- Combination Therapy Using Phytochemicals and PARP Inhibitors in Hybrid Nanocarriers: An Optimistic Approach for the Management of Colon Cancer.International journal of molecular sciences · 2025Review
- Over Two Years of Sustained Remission With Olaparib Monotherapy in Stage IV Non-Small Cell Lung Cancer With ATM Mutation: A Case Report.Cancer reports (Hoboken, N.J.) · 2025Article
- piscesCSM: prediction of anticancer synergistic drug combinations.Journal of cheminformatics · 2024Article
- PARP Inhibitors in Colorectal Malignancies: A 2023 Update.Reviews on recent clinical trials · 2024Review
- A carrier-free supramolecular nano-twin-drug for overcoming irinotecan-resistance and enhancing efficacy against colorectal cancer.Journal of nanobiotechnology · 2023Article
- Germline variants of uncertain significance, their frequency, and clinico-pathological features in a cohort of Sri Lankan patients with hereditary breast cancer.BMC research notes · 2023Article
- Evolution of Resistance to Irinotecan in Cancer Cells Involves Generation of Topoisomerase-Guided Mutations in Non-Coding Genome That Reduce the Chances of DNA Breaks.International journal of molecular sciences · 2023Article
- Resistance to TOP-1 Inhibitors: Good Old Drugs Still Can Surprise Us.International journal of molecular sciences · 2023Review
- MGAE-DC: Predicting the synergistic effects of drug combinations through multi-channel graph autoencoders.PLoS computational biology · 2023Article
- Molecular Subtypes Based on Cuproptosis-Related Genes and Tumor Microenvironment Infiltration Characterization in Colorectal Cancer.Journal of oncology · 2022Article
- Implications of Intratumor Heterogeneity on Consensus Molecular Subtype (CMS) in Colorectal Cancer.Cancers · 2021Article
- Review
- Recent Research Progress of Chiral Small Molecular Antitumor-Targeted Drugs Approved by the FDA From 2011 to 2019.Frontiers in oncology · 2021Review
Corrections and comments
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Authors and funding
20 authors at 1 institution in 1 country.
Funding
Abstract
backgroundDespite the advancements in new therapies for colorectal cancer (CRC), chemotherapy still constitutes the mainstay of the medical treatment. For this reason, new strategies to increase the efficacy of chemotherapy are desirable. Poly-ADP-Ribose Polymerase inhibitors (PARPi) have shown to increase the activity of DNA damaging chemotherapeutics used in the treatment of CRC, however previous clinical trials failed to validate these results and pointed out dose-limiting toxicities that hamper the use of such combinations in unselected CRC patients. Nevertheless, in these studies little attention was paid to the mutational status of homologous recombination repair (HRR) genes.
methodsWe tested the combination of the PARPi niraparib with either 5-fluorouracil, oxaliplatin or irinotecan (SN38) in a panel of 12 molecularly annotated CRC cell lines, encompassing the 4 consensus molecular subtypes (CMSs). Synergism was calculated using the Chou-Talalay method for drug interaction. A correlation between synergism and genetic alterations in genes involved in homologous recombination (HR) repair was performed. We used clonogenic assays, mice xenograft models and patient-derived 3D spheroids to validate the results. The induction of DNA damage was studied by immunofluorescence.
resultsWe showed that human CRC cell lines, as well as patient-derived 3D spheroids, harboring pathogenic ATM mutations are significantly vulnerable to PARPi/chemotherapy combination at low doses, regardless of consensus molecular subtypes (CMS) and microsatellite status. The strongest synergism was shown for the combination of niraparib with irinotecan, and the presence of ATM mutations was associated to a delay in the resolution of double strand breaks (DSBs) through HRR and DNA damage persistence.
conclusionsThis work demonstrates that a numerically relevant subset of CRCs carrying heterozygous ATM mutations may benefit from the combination treatment with low doses of niraparib and irinotecan, suggesting a new potential approach in the treatment of ATM-mutated CRC, that deserves to be prospectively validated in clinical trials.
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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.