The Effect of Xevinapant Combined with Ionizing Radiation on HNSCC and Normal Tissue Cells and the Impact of Xevinapant on Its Targeted Proteins cIAP1 and XIAP
The poor prognosis of head and neck squamous cell carcinoma (HNSCC) is partly attributed to treatment resistance. Xevinapant, a SMAC mimetic, represents a promising targeted cancer therapy. By inhibiting cIAP1/2 and XIAP, Xevinapant promotes apoptosis, necroptosis, and suppresses prosurvival signaling pathways. Its combination with ionizing radiation (IR) holds potential for enhanced therapeutic efficacy. This study investigated the effects of Xevinapant and IR on HNSCC and healthy tissue cells by assessing cell growth, cell death, clonogenic survival, and DNA double-strand breaks (DSBs), along with intracellular cIAP1 and XIAP levels.
Xevinapant exhibited both cytostatic and cytotoxic effects, as well as radiosensitizing properties in malignant cells, while sparing healthy tissue cells to a greater extent. The drug notably increased apoptotic and necrotic cell death. Furthermore, its association with elevated residual DSBs and reduced cell survival suggested an impact on DNA damage repair and other cell inactivation mechanisms. The levels of cIAP1 and XIAP varied among cell lines and were influenced by Xevinapant and IR treatment. Notably, higher IAP levels were linked to increased cell death.
These findings highlight Xevinapant as a potent therapeutic candidate for HNSCC, particularly when combined with IR. Additionally, IAP levels may serve as biomarkers for impaired DNA damage repair and heightened cellular stress sensitivity.