The dual PI3K/mTOR inhibitor PKI-587 enhances sensitivity to cetuximab in EGFR-resistant human head and neck cancer models

• Published in: British journal of cancer 2014-06, Vol.110 (12), p.2887-2895
• Main Authors: D'Amato, V, Rosa, R, D'Amato, C, Formisano, L, Marciano, R, Nappi, L, Raimondo, L, Di Mauro, C, Servetto, A, Fusciello, C, Veneziani, B M, De Placido, S, Bianco, R
• Format: Article
• Language: English
• Subjects: 692/699/67/1059/2325; 692/699/67/1536; 692/700/565/1436/1437; Animals; Antibodies, Monoclonal, Humanized - pharmacology; Antineoplastic Agents - pharmacology; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis; Apoptosis - drug effects; Autophagy - drug effects; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cancer therapies; Carcinoma, Squamous Cell - drug therapy; Caspase 3 - biosynthesis; Cell division; Cell Line, Tumor; Cell Proliferation - drug effects; Cetuximab; Drug Resistance; Drug Resistance, Neoplasm; Epidemiology; Epidermal growth factor; ErbB Receptors - antagonists & inhibitors; Head & neck cancer; Head and Neck Neoplasms - drug therapy; Humans; Medical prognosis; Medical sciences; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Medicine; Morpholines - pharmacology; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Mutation; Oncology; Otorhinolaryngology (head neck, general aspects and miscellaneous); Otorhinolaryngology. Stomatology; Pathogenesis; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Squamous Cell Carcinoma of Head and Neck; TOR Serine-Threonine Kinases - antagonists & inhibitors; Translational Therapeutics; Triazines - pharmacology; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2014.241

Background: 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. As the phosphoinositide 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) pathways have an important role in the pathogenesis of HNSCC, we investigated their involvement in cetuximab resistance. Methods: 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 . Results: Treatment with PKI-587 enhances sensitivity to cetuximab in vitro , even in the condition of epidermal growth factor receptor (EGFR) resistance. The combination of the two drugs inhibits cells survival, impairs the activation of signalling 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 pre-eminent. In nude mice xenografted with resistant Kyse30 cells, the combined treatment significantly reduces tumour growth and prolongs mice survival. Conclusions: Phosphoinositide 3-kinase/mammalian target of rapamycin inhibition has an important role in the rescue of cetuximab resistance. Different mechanisms of cell death are induced by combined treatment depending on basal anti-EGFR responsiveness.