Since NOTCH1 is inactivated in approximately one-tenth of SCCHN cases, and this aberration is a powerful activator of the AKT pathway and a negative regulator of HER3, exclusion of patients bearing NOTCH1-inactivated SCCHN tumors may be recommended for future clinical trials on HER3-targeting antibodies. The gene discussed is NOTCH1; the disease is head and neck squamous cell carcinoma.