CFI-400945 enhances radiosensitivity in colorectal cancer models by promoting mitotic dysregulation and DNA damage-associated apoptosis.
7 affiliations
- 1Department of Surgery, Keimyung University School of Medicine, Daegu, 1095, Republic of Korea.
- 2Department of Pathology, Keimyung University School of Medicine, Daegu, 1095, Republic of Korea.
- 3Department of Immunology, Keimyung University School of Medicine, Daegu, Republic of Korea.
- 4Department of Radiation Oncology, Keimyung University School of Medicine, Daegu, 1095, Republic of Korea.
- 5Department of Anatomy, Keimyung University School of Medicine, Daegu, 1095, Republic of Korea. [email protected].
- 6Department of Pathology, Keimyung University School of Medicine, Daegu, 1095, Republic of Korea. [email protected].
- 7Department of Surgery, School of Medicine & Institute for Medical Science, Keimyung University Dongsan Medical Center, Daegu, Korea. [email protected].
Abstract
Background
Radioresistance remains a major barrier to improving radiotherapy (RT) efficacy in colorectal cancer (CRC). Since mitotic fidelity and centrosome homeostasis influence cell fate under genotoxic stress, we investigated whether CFI-400945 enhances the radiation response in CRC models and whether this effect is associated with polo-like kinase 4 (PLK4)-related mitotic dysregulation.Methods
HCT116 and HT29 CRC cells were treated with CFI-400945 and/or irradiation. Radiation response was evaluated using MTT viability and clonogenic survival assays, alongside analyses of cell-cycle distribution, centrosome-associated abnormalities, nuclear phenotypes, DNA damage-associated signaling, and apoptotic markers. PLK4 involvement was evaluated using siRNA-mediated PLK4 depletion, and Aurora kinase B (AURKB) phosphorylation was assessed to examine potential Aurora B-related effects. Combination treatment was also tested in non-malignant CCD 841 CoN colon-derived control cells and patient-derived CRC organoids.Results
Combined CFI-400945 and RT treatment reduced short-term viability and long-term clonogenic survival in HCT116 and HT29 cells compared with either monotherapy. In CCD 841 CoN cells, CFI-400945 did not significantly enhance radiation-associated loss of clonogenic survival versus RT alone. Combination treatment increased G2/M accumulation, >4 N and sub-G1 fractions, γ-tubulin-positive foci, multinucleation, and micronucleation, consistent with centrosome-associated mitotic abnormalities and reduced survival. DNA damage-associated signaling was enhanced, with increased DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and phosphorylated histone H2AX (γH2AX) levels and increased phosphorylation of ataxia telangiectasia mutated (ATM) and CHK2. Apoptotic marker induction also increased, including robust cleavage of caspase-3 and PARP1. CFI-400945 did not markedly suppress AURKB phosphorylation under the experimental conditions. Importantly, siRNA-mediated PLK4 depletion reduced clonogenic survival after irradiation and increased cleaved PARP1 and cleaved caspase-3, supporting PLK4 involvement in the radiation response. In patient-derived CRC organoids, combination treatment reduced viability and increased DNA damage-associated and apoptotic markers compared with single treatments.Conclusions
CFI-400945 enhanced radiation response in CRC cell lines and patient-derived organoids, accompanied by centrosome-associated mitotic abnormalities, increased DNA damage-associated signaling, and apoptotic marker induction. siRNA-mediated PLK4 depletion partially recapitulated these effects, supporting a role for PLK4-associated mitotic regulation. However, because CFI-400945 may also target non-PLK4 mitotic kinases, these support an association --between radiosensitization and PLK4-related mitotic dysregulation rather than an exclusively PLK4-dependent mechanism.
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BibTeX
@article{hwang2026cfi400945,
title = {{CFI-400945 enhances radiosensitivity in colorectal cancer models by promoting mitotic dysregulation and DNA damage-associated apoptosis.}},
author = {Jeong-Woo Hwang and Eun-Young Gong and Jae-Min Cho and Shin Kim and Sang Jun Byun and Hyowon Hong and Hye Won Lee and Sung Uk Bae},
journal = {Cancer cell international},
year = {2026},
month = jul,
doi = {10.1186/s12935-026-04407-y},
url = {https://europepmc.org/article/MED/42894194},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - CFI-400945 enhances radiosensitivity in colorectal cancer models by promoting mitotic dysregulation and DNA damage-associated apoptosis.
AU - Jeong-Woo Hwang
AU - Eun-Young Gong
AU - Jae-Min Cho
AU - Shin Kim
AU - Sang Jun Byun
AU - Hyowon Hong
AU - Hye Won Lee
AU - Sung Uk Bae
PY - 2026
DA - 2026/07/01
JO - Cancer cell international
DO - 10.1186/s12935-026-04407-y
UR - https://europepmc.org/article/MED/42894194
AB - Background Radioresistance remains a major barrier to improving radiotherapy (RT) efficacy in colorectal cancer (CRC). Since mitotic fidelity and centrosome homeostasis influence cell fate under genotoxic stress, we investigated whether CFI-400945 enhances the radiation response in CRC models and whether this effect is associated with polo-like kinase 4 (PLK4)-related mitotic dysregulation.Methods HCT116 and HT29 CRC cells were treated with CFI-400945 and/or irradiation. Radiation response was evaluated using MTT viability and clonogenic survival assays, alongside analyses of cell-cycle distribution, centrosome-associated abnormalities, nuclear phenotypes, DNA damage-associated signaling, and apoptotic markers. PLK4 involvement was evaluated using siRNA-mediated PLK4 depletion, and Aurora kinase B (AURKB) phosphorylation was assessed to examine potential Aurora B-related effects. Combination treatment was also tested in non-malignant CCD 841 CoN colon-derived control cells and patient-derived CRC organoids.Results Combined CFI-400945 and RT treatment reduced short-term viability and long-term clonogenic survival in HCT116 and HT29 cells compared with either monotherapy. In CCD 841 CoN cells, CFI-400945 did not significantly enhance radiation-associated loss of clonogenic survival versus RT alone. Combination treatment increased G2/M accumulation, >4 N and sub-G1 fractions, γ-tubulin-positive foci, multinucleation, and micronucleation, consistent with centrosome-associated mitotic abnormalities and reduced survival. DNA damage-associated signaling was enhanced, with increased DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and phosphorylated histone H2AX (γH2AX) levels and increased phosphorylation of ataxia telangiectasia mutated (ATM) and CHK2. Apoptotic marker induction also increased, including robust cleavage of caspase-3 and PARP1. CFI-400945 did not markedly suppress AURKB phosphorylation under the experimental conditions. Importantly, siRNA-mediated PLK4 depletion reduced clonogenic survival after irradiation and increased cleaved PARP1 and cleaved caspase-3, supporting PLK4 involvement in the radiation response. In patient-derived CRC organoids, combination treatment reduced viability and increased DNA damage-associated and apoptotic markers compared with single treatments.Conclusions CFI-400945 enhanced radiation response in CRC cell lines and patient-derived organoids, accompanied by centrosome-associated mitotic abnormalities, increased DNA damage-associated signaling, and apoptotic marker induction. siRNA-mediated PLK4 depletion partially recapitulated these effects, supporting a role for PLK4-associated mitotic regulation. However, because CFI-400945 may also target non-PLK4 mitotic kinases, these support an association --between radiosensitization and PLK4-related mitotic dysregulation rather than an exclusively PLK4-dependent mechanism.
SN - 1475-2867
ER -