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Genetic Factors in Colorectal Cancer / DNA Repair Mechanisms · Journal article
Cell Death Discovery · September 9, 2026
Raises a question worth testing. It does not answer one.
This is an in vitro mechanistic study demonstrating that CHK2 deficiency in HCT116 cancer cells alters the engagement of DNA repair pathways, with increased homologous recombination repair frequency despite compromised RAD51 foci formation, and differential sensitivity to pathway-specific inhibitors. The findings are exploratory and raise questions about the interplay between CHK2 status and radiation response that require further investigation.
In vitro mechanistic study using isogenic cancer cell lines. HCT116 colorectal cancer cells with CHK2 knockout or wild-type status; cancer cell lines with distinct CHK2 alterations were included in inhibitor studies. Intervention: CHK2 knockout (genetic) and pathway inhibitors (peposertib for DNA-PKcs/NHEJ; CAM833 for RAD51/HRR) combined with ionizing radiation. Compared with: CHK2 wild-type isogenic cells; ionizing radiation alone.
CHK2-deficient HCT116 cells exhibit higher homologous recombination repair frequency than CHK2-proficient cells despite compromised RAD51 foci formation Transcriptomics analysis revealed significantly decreased DNA-PKcs expression and increased NBS1 mRNA levels in CHK2 KO cells compared to CHK2 WT cells NHEJ inhibitor peposertib further decreased viability of CHK2-proficient cells compared to ionizing radiation alone
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These findings are preliminary and do not yet support clinical recommendations. The authors conclude that CHK2 alterations warrant further study to determine their significance in shaping radiation response and inform potential combination therapy strategies.
A mechanistic study in cell lines showing how CHK2 deficiency alters DNA repair pathway engagement; findings are exploratory and require further investigation to establish clinical relevance.
As stated by the source record.
These findings are preliminary and do not yet support clinical recommendations. The authors conclude that CHK2 alterations warrant further study to determine their significance in shaping radiation response and inform potential combination therapy strategies.
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Abstract Checkpoint kinase 2 (CHK2) participates in the DNA damage response (DDR) by regulating the cell cycle or inducing apoptosis, and its abnormal activity can lead to cancer development. CHK2 loss-of-function mutations correlate with the onset of many types of tumors and with therapy resistance. As the exact molecular mechanisms underlying these phenomena are not fully elucidated, we aimed to understand how CHK2 deficiency in cancer cells affects their DDR functionality and their DNA repair ability post-treatment. Despite compromised RAD51 foci formation, we found that CHK2 -deficient HCT116 cancer cells exhibit higher homologous recombination repair (HRR) frequency than CHK2 -proficient cells. Transcriptomics analysis revealed a significantly decreased expression of DNA-PKcs and increased NBS1 mRNA levels in CHK2 knockout (KO) cells compared to their isogenic CHK2 WT line. These changes were also confirmed on a protein level. Consequently, the repression of the NHEJ pathway by the DNA-PKcs small molecule inhibitor peposertib further decreased the viability of HCT116 CHK2 -proficient cells compared to ionizing radiation alone, while the blockage of HRR by the RAD51 inhibitor CAM833 did not radiosensitize cancer cell lines with distinct CHK2 alterations. In conclusion, our results indicate that CHK2 KO influences DNA repair pathways engagement, and the targeting of these pathways in combination with irradiation deserves further studies to uncover the significance of CHK2 alterations in shaping radiation response.
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