ArticleClinical cancer research : an official journal of the American Association for Cancer Research2022
Targeting the DNA Damage Response Pathways and Replication Stress in Colorectal Cancer.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers, 1 of them a synthesis that pooled it.
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Who cites it
40 citing papers in PubMed, 1 synthesis or guideline pooled it, 57 citations in OpenAlex.
- A comprehensive overview of the molecular features and therapeutic targets in BRAFClinical and translational medicine · 2024Pooled it
- Tumour hypoxia in clinical oncology: imaging, therapeutic strategies, and translational challenges.Clinical and translational radiation oncology · 2027Review
- WEE1 kinase inhibition to overcome acquired resistance to targeted therapies in colorectal cancer.EMBO molecular medicine · 2026Article
- Synthetic lethality and DNA damage response targeting in cancer stem cells: a comprehensive review.Discover oncology · 2026Review
- The Molecular and Functional Landscape of Resistance to FOLFIRI Chemotherapy in Metastatic Colorectal Cancer.Cancer discovery · 2026Article
- Common gene mutations in 103 authenticated colorectal cancer cell lines.Oncogenesis · 2026Article
- NSMF modulates replication stress to facilitate colorectal cancer progression.Nucleic acids research · 2026Article
- Multi-omics insights into SERPINE2-driven post-metastatic microenvironmental reprogramming in advanced cancers: implications for molecular targeting and immunotherapy.Frontiers in immunology · 2026Review
- Integrative Bioinformatics and Experimental Validation Establish CCNB1 as a Potential Biomarker for Diagnosis and Prognosis in Colorectal Cancer.Current issues in molecular biology · 2025Article
- Targeting theBiomedicines · 2025Article
- Cuproptosis: the mechanisms of copper-induced cell death and its implication in colorectal cancer.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- TRPM8 levels determine tumor vulnerability to channel agonists.Molecular oncology · 2025Article
- C1orf116 inhibits acquired resistance to EGFR inhibitors in EGFR mutant lung adenocarcinoma by suppressing the ATM/ATR pathways.Translational lung cancer research · 2025Article
- Combining BET inhibition with SMAC mimetics restricts tumor growth and triggers immune surveillance in preclinical cancer models.Cell reports. Medicine · 2025Article
- UCHL3: a crucial deubiquitinase in DNA damage repair and tumor progression.Cancer cell international · 2025Review
- Germline genomic profiling of patients with early-onset colorectal cancer.ESMO gastrointestinal oncology · 2025Article
- Krüppel-like Factor 4-Deficient Cells Are Sensitive to Etoposide-Induced DNA Damage.Current issues in molecular biology · 2025Article
- Carbon ion irradiation conquers the radioresistance by inducing complex DNA damage and apoptosis in U251 human glioblastomas cells.Medical oncology (Northwood, London, England) · 2025Article
- Cell cycle proteins: Linking the cell cycle to tumors.Oncology research · 2025Review
- Exploiting replication stress for synthetic lethality in MYC-driven cancers.American journal of cancer research · 2025Review
Corrections and comments
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Authors and funding
23 authors at 6 institutions in 4 countries.
Funding
Abstract
purposeGenomic instability is a hallmark of cancer and targeting DNA damage response (DDR) is emerging as a promising therapeutic strategy in different solid tumors. The effectiveness of targeting DDR in colorectal cancer has not been extensively explored. EXPERIMENTAL
designWe challenged 112 cell models recapitulating the genomic landscape of metastatic colorectal cancer with ATM, ATR, CHK1, WEE1, and DNA-PK inhibitors, in parallel with chemotherapeutic agents. We focused then on ATR inhibitors (ATRi) and, to identify putative biomarkers of response and resistance, we analyzed at multiple levels colorectal cancer models highly sensitive or resistant to these drugs.
resultsWe found that around 30% of colorectal cancers, including those carrying KRAS and BRAF mutations and unresponsive to targeted agents, are sensitive to at least one DDR inhibitor. By investigating potential biomarkers of response to ATRi, we found that ATRi-sensitive cells displayed reduced phospho-RPA32 foci at basal level, while ATRi-resistant cells showed increased RAD51 foci formation in response to replication stress. Lack of ATM and RAD51C expression was associated with ATRi sensitivity. Analysis of mutational signatures and HRDetect score identified a subgroup of ATRi-sensitive models. Organoids derived from patients with metastatic colorectal cancer recapitulated findings obtained in cell lines.
conclusionsIn conclusion, a subset of colorectal cancers refractory to current therapies could benefit from inhibitors of DDR pathways and replication stress. A composite biomarker involving phospho-RPA32 and RAD51 foci, lack of ATM and RAD51C expression, as well as analysis of mutational signatures could be used to identify colorectal cancers likely to respond to ATRi.
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