HNSCC lesions often harbor activating mutations in PIK3CA (18.1 %), encoding the catalytic PI3K-α subunit and less frequent oncogenic mutants of the HRAS (5.6 %) or KRAS (0.2 %) genes [8, 12], collectively referred herein as RAS. To explore whether the combination of rapamycin and trametinib also displays synergistic effect in HNSCC tumors harboring activating mutations of RAS and PIK3CA, we evaluated the impact of this drug combination in HNSCC cells harboring endogenous oncogenic mutations. The gene discussed is PIK3CA; the disease is head and neck squamous cell carcinoma.