In search for the underlying mechanisms sustaining elevated PI3K-AKT-mTOR activity in HNSCC cells that do not harbor PIK3CA mutations, we took advantage of the fact that signaling inhibitors are growth suppressive in HNSCC to conduct a kinome-wide siRNA screen in a PIK3CA wild type HNSCC cell line (Fig. 1a). The gene discussed is PIK3CA; the disease is head and neck squamous cell carcinoma.