Effect of complementary pathway blockade on efficacy of combination enzastaurin and rapamycin.

Abstract

BACKGROUND:

Rapamycin is an mTOR inhibitor with preclinical efficacy in squamous cell carcinoma of the head and neck (SCCHN). However, mTOR inhibitors also increase Akt activity in SCCHN cell lines, which would promote survival and oncogenesis. Enzastaurin is an AGC kinase inhibitor with nanomolar inhibitory concentrations for Akt and protein kinase C (PKC). Moreover, Akt and PKC inhibitors have demonstrated efficacy in SCCHN.

METHODS:

We hypothesized that the combination of rapamycin and enzastaurin would be more effective than either agent alone.

RESULTS:

Rapamycin and enzastaurin generally inhibited putative targets in SCCHN cell lines in culture. In mice xenografted with CAL27 cells, rapamycin and enzastaurin produced growth delay. In contrast, the combination of rapamycin and enzastaurin caused regression of CAL27 tumors with evidence of inhibition of putative targets, survival, angiogenesis and proliferation.

CONCLUSION:

These data demonstrate that the combination of rapamycin and enzastaurin disrupts critical oncogenic pathways in SCCHN and has efficacy in preclinical models.

• Authors: Jing Liu, Wen-Liang Kuo, Tanguy Y Seiwert, Mark Lingen, Mark F Ciaccio, Richard B Jones, Marsha Rich Rosner, Ezra Eddy Wyssam Cohen
• Journal: Head & neck (Head Neck) Vol. 33 Issue 12 Pg. 1774-82 (Dec 2011) ISSN: 1097-0347 [Electronic] United States
• PMID: 21438065 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 Wiley Periodicals, Inc.

Chemical References

• Antibiotics, Antineoplastic
• Indoles
• Protein Kinase Inhibitors
• TOR Serine-Threonine Kinases
• enzastaurin
• Sirolimus

Topics

• Animals
• Antibiotics, Antineoplastic (pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Squamous Cell (blood supply, drug therapy, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Synergism
• Female
• Head and Neck Neoplasms (blood supply, drug therapy, pathology)
• In Situ Nick-End Labeling
• Indoles (pharmacology)
• MAP Kinase Signaling System (drug effects)
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Neovascularization, Pathologic
• Protein Kinase Inhibitors (pharmacology)
• Sirolimus (pharmacology)
• Squamous Cell Carcinoma of Head and Neck
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Tumor Cells, Cultured