Apatinib resistance mediated by IRF9 nuclear translocation in head and neck squamous cell carcinoma.

Apatinib is being increasingly utilized in the treatment of head and neck squamous cell carcinoma (HNSCC) patients. However, clinical resistance to apatinib is commonly observed, the underlying mechanism remains unclear. In this study, we established apatinib-resistant HNSCC cell lines and performed SPIA (small molecule protein interaction assay) to identify interferon regulatory factor 9 (IRF9) as a critical determinant of drug resistance. Mechanistically, apatinib binds to IRF9, enhancing protein flexibility and ability to bind the nuclear transport protein RAN and translocate into the nucleus. Once translocated, IRF9 facilitates tumor progression by the basal cell carcinoma pathway and the JAK-STAT signaling pathway. HY-N1435 (Oroxin B), a small-molecule drug targeting IRF9, was found to reverse apatinib resistance in HNSCC. Moreover, higher IRF9 protein expression levels are associated with an increased likelihood of apatinib resistance. Taken together, the current study provided critical insights into the apatinib resistance mechanisms of HNSCC and proposed therapeutic strategies.