Abstract | BACKGROUND: 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:
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Authors | V D'Amato, R Rosa, C D'Amato, L Formisano, R Marciano, L Nappi, L Raimondo, C Di Mauro, A Servetto, C Fusciello, B M Veneziani, S De Placido, R Bianco |
Journal | British journal of cancer
(Br J Cancer)
Vol. 110
Issue 12
Pg. 2887-95
(Jun 10 2014)
ISSN: 1532-1827 [Electronic] England |
PMID | 24823695
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antibodies, Monoclonal, Humanized
- Antineoplastic Agents
- Morpholines
- Phosphoinositide-3 Kinase Inhibitors
- Triazines
- gedatolisib
- MTOR protein, human
- ErbB Receptors
- TOR Serine-Threonine Kinases
- Caspase 3
- Cetuximab
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Topics |
- Animals
- Antibodies, Monoclonal, Humanized
(pharmacology)
- Antineoplastic Agents
(pharmacology)
- Antineoplastic Combined Chemotherapy Protocols
(pharmacology)
- Apoptosis
(drug effects)
- Autophagy
(drug effects)
- Carcinoma, Squamous Cell
(drug therapy)
- Caspase 3
(biosynthesis)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Cetuximab
- Drug Resistance, Neoplasm
- ErbB Receptors
(antagonists & inhibitors)
- Head and Neck Neoplasms
(drug therapy)
- Humans
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Morpholines
(pharmacology)
- Phosphoinositide-3 Kinase Inhibitors
- Squamous Cell Carcinoma of Head and Neck
- TOR Serine-Threonine Kinases
(antagonists & inhibitors)
- Triazines
(pharmacology)
- Xenograft Model Antitumor Assays
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