Abstract Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related mortality worldwide. Radiotherapy (RT) is a mainstay of treatment; however, the frequent development of radioresistance limits its therapeutic efficacy. Polo-like kinase 4 (PLK4), a master regulator of centriole duplication and centrosome integrity, has been implicated in chromosomal instability, DNA damage responses (DDR), and epithelial-mesenchymal transition (EMT). Therefore, targeting PLK4 may represent a novel strategy to overcome radioresistance. In this study, we investigated the effects of the selective PLK4 inhibitor CFI-400945 in NSCLC cells exposed to RT. CFI-400945 treatment significantly reduced cell viability and clonogenic survival in combination with RT compared to either treatment alone. Mechanistically, CFI-400945 amplified apoptotic signaling, with marked upregulation of p53 and cleaved PARP1. In addition, PLK4 inhibition promoted G2/M cell cycle arrest by reducing RT-induced p-AKT and cyclin B1 expression level. Furthermore, PLK4 inhibition enhanced RT-induced DNA damage as indicated by increased γH2AX expression. Importantly, RT alone promoted EMT progression, characterized by reduced E-cadherin and increased N-cadherin and vimentin expression, as well as enhanced migratory capacity. These effects were significantly reversed by CFI-400945, indicating that PLK4 inhibition attenuates RT-induced EMT progression. Collectively, these findings demonstrate that PLK4 inhibition with CFI-400945 sensitizes NSCLC cells to RT by augmenting DNA damage and apoptosis while suppressing RT-induced EMT. Our results highlight PLK4 as a critical regulator linking centrosome abnormalities, DDR, and EMT, and suggest that combining PLK4 inhibition with RT may provide a promising therapeutic approach to overcome radioresistance in NSCLC. Citation Format: Hye Won Lee, Shin Kim, Jeong-Woo Hwang, Eun-Young Gong, Hyowon Hong, SangJun Byun, Sung Uk Bae. Polo-like kinase 4 inhibition enhances radiosensitivity in non-small cell lung cancer via apoptosis and epithelial-mesenchymal transition regulation abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6393.
Lee et al. (Fri,) studied this question.