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

Jing Liu, Wen Liang Kuo, Tanguy Y. Seiwert, Mark Lingen, Mark F. Ciaccio, Richard B. Jones, Marsha Rich Rosner, Ezra Eddy Wyssam Cohen

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1774-1782
Number of pages9
JournalHead and Neck
Volume33
Issue number12
DOIs
StatePublished - Dec 1 2011
Externally publishedYes

Keywords

  • AKT
  • Head and neck squamous cell carcinoma
  • PKC
  • enzastaurin
  • mTOR
  • rapamycin

ASJC Scopus subject areas

  • Otorhinolaryngology

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