Through validation experiments utilising spheroid growth assays in FaDu cells and subsequent clonogenic survival assays in multiple HPV-negative HNSCC cell lines (FaDu, A253, and UMSCC11b), we confirmed that the broad-spectrum HDAC inhibitor pracinostat and the multi-targeted EGFR and HDAC inhibitor CUDC-101 can potentiate the effects of X-rays in HNSCC cell killing. Here, EGFR is linked to head and neck squamous cell carcinoma.