SINTESI CONTENENTE UNA BREVE DESCRIZIONE DEL LAVORO SVOLTO E DEI RISULTATI OTTENUTI: Cetuximab is the only targeted agent approved for the treatment of head and neck squamous cell carcinomas (HNSCC), but low response rates and disease progression are frequently reported. Since the phosphoinositide 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) pathways play an important role in the pathogenesis of HNSCC, we investigated their involvement in cetuximab resistance. Different human squamous cancer cell lines sensitive or resistant to cetuximab were tested for the dual PI3K/mTOR inhibitor PF-05212384 (PKI-587), alone and in combination, both in vitro and in vivo. Treatment with PKI-587 enhances sensitivity to cetuximab in vitro, even in condition of EGFR-resistance. The combination of the two drugs inhibits cells survival, impairs the activation of signaling pathways and induces apoptosis. Interestingly, although significant inhibition of proliferation is observed in all cell lines treated with PKI-587 in combination with cetuximab, activation of apoptosis is evident in sensitive but not in resistant cell lines, in which autophagy is preeminent. In nude mice xenografted with resistant Kyse30 cells, the combined treatment significantly reduces tumor growth and prolongs mice survival. PI3K/mTOR inhibition plays an important role in the rescue of cetuximab resistance. Different mechanism of cell death are induced by combined treatment depending on basal anti-EGFR responsiveness.