Evaluation of crizotinib as radiosensitizer in sacral chordoma cells: effects of combined carbon ion particle therapy

Chordoma resection is challenging due to proximity to the brainstem or spinal cord, and chemotherapy offers limited efficacy. Combining surgery with radiotherapy, particularly using carbon ions (C-ions) for their higher biological effectiveness, improves local control and survival rates. To investigate cellular mechanisms, two human sacral chordoma cell lines were irradiated with varying C-ions doses. Growth, cell cycle, DNA damage response, and protein phosphorylation were analyzed using flow cytometry, protein, and gene expression profiling. The potential of combining treatment with the ALK/MET inhibitor crizotinib to enhance radiosensitivity was also evaluated. C-ions irradiation resulted in a slight dose-dependent decrease in proliferation, a clear G₂/M cell cycle arrest, and a significant activation of key regulators involved in DNA repair and damage response. The ALK/MET inhibitor crizotinib, considered a potential treatment for chordomas, reduced proliferation markers and modulated important genes related to DNA repair and cell cycle regulation, with CDC20 and FOXO4 being particularly significant. The phosphorylation of key regulators involved in DNA repair and damage prevention, as well as MAPKs activated by C-ions irradiation, was partially inhibited by the combination treatment with crizotinib. While crizotinib shows promise as a therapeutic agent for sacral chordomas, its capacity to enhance radiosensitivity appears limited.