<scp>AKT</scp> , <scp>ATR</scp> , and Notch Inhibitors Radiosensitize a Preclinical Model of Adenoid Cystic Carcinoma

ABSTRACT Background Adenoid Cystic Carcinoma (ACC) is a rare and lethal type of head and neck cancer. Standard therapy involves surgery followed by radiation therapy. The majority of ACC has MYB overexpression and MYB‐NFIB gene fusions, while Notch mutations are associated with aggressive behavior. Targeted therapies against these drivers or their downstream targets have been incompletely explored, especially in combination with radiation. Methods cBioPortal was used for genomic and survival analyses. MYB, AKT, ATR, NOTCH, and NFIB expression was assessed via RNA‐seq, qRT‐PCR, and western blot. Radiation sensitization was evaluated by clonogenic assays while the effect on DNA damage was tested using γH2AX and RAD51 foci assays. Results MYB, ATR, AKT1, Notch1, Notch2, and NFIB are overexpressed in ACC tumors, PDX, and cell lines. ACC patients with ATR, AKT, MYB, and NFIB alterations have poor overall survival. ATR, AKT, and Notch inhibitors sensitized UM‐HACC2A cells to radiation. Drugs and radiation combination reduced target mRNA expression. Conclusion ATR, AKT, and Notch inhibitors radiosensitize a preclinical model of ACC.