Through this screen and subsequent validation experiments, we discovered that the HDAC inhibitors mocetinostat and pracinostat and the combined HDAC–epidermal growth factor receptor (EGFR) inhibitor CUDC-101 improved the sensitivity of 3D and 2D models of HPV-negative HNSCC cells to X-ray irradiation. Here, EGFR is linked to head and neck squamous cell carcinoma.