CFI-400945 enhances radiosensitivity in colorectal cancer models by promoting mitotic dysregulation and DNA damage-associated apoptosis.

Authors

Jeong-Woo Hwang, Eun-Young Gong, Jae-Min Cho, Shin Kim, Sang Jun Byun, Hyowon Hong, Hye Won Lee, Sung Uk Bae

Published in

Cancer cell international. Volume 26. Issue 1. Jul 22, 2026. Epub Jul 22, 2026.

Abstract

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.
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.
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.
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.

PMID:
42894194
Bibliographic data and abstract were imported from PubMed on 19 Oct 2026.

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