We found a higher rate of gene mutations with putative protein-changing characteristics in non-responders, mutational profiles of responders and non-responders that allow stratification of HNSCC patients, and pharmacological inhibition of Kelch Like ECH Associated Protein 1 (KEAP1) and mechanistic target of rapamycin (mTOR) to effectively diminish non-responder insusceptibility to β1 integrin and EGFR targeting for radiosensitization. The gene discussed is KEAP1; the disease is head and neck squamous cell carcinoma.