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

AbstractBACKGROUND:
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.
AuthorsV 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
JournalBritish journal of cancer (Br J Cancer) Vol. 110 Issue 12 Pg. 2887-95 (Jun 10 2014) ISSN: 1532-1827 [Electronic] England
PMID24823695 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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
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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