The dual PI3K/mTOR inhibitor PKI-587 enhances sensitivity to cetuximab in EGFR-resistant human head and neck cancer models.
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.
1] Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli 'Federico II', Naples, Italy [2] IRCCS Multimedica-Bioker, Milano, Italy.
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D'Amato
1] Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli 'Federico II', Naples, Italy [2] IRCCS Multimedica-Bioker, Milano, Italy.
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Rosa
Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli 'Federico II', Naples, Italy.
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D'Amato
Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli 'Federico II', Naples, Italy.
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Formisano
Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli 'Federico II', Naples, Italy.
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Marciano
1] Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli 'Federico II', Naples, Italy [2] Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
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Nappi
Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli 'Federico II', Naples, Italy.
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Raimondo
Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli 'Federico II', Naples, Italy.
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Di Mauro
Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli 'Federico II', Naples, Italy.
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Servetto
Dipartimento di Medicina e Chirurgia Campus di Baronissi, Università degli Studi di Salerno, Salerno, Italy.
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Fusciello
Dipartimento di Medicina molecolare e Biotecnologie mediche, Università degli studi di Napoli 'Federico II', Naples, Italy.
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Veneziani
Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli 'Federico II', Naples, Italy.
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De Placido
Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli 'Federico II', Naples, Italy.
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Bianco
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D053148:Caspase 3 / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000077195:Squamous Cell Carcinoma of Head and Neck; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014227:Triazines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014227:Triazines; C549060:gedatolisib; C546842:MTOR protein, human; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases; D053148:Caspase 3; D000068818:Cetuximab