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Effect of complementary pathway blockade on efficacy of combination enzastaurin and rapamycin
Author(s) -
Liu Jing,
Kuo WenLiang,
Seiwert Tanguy Y.,
Lingen Mark,
Ciaccio Mark F.,
Jones Richard B.,
Rosner Marsha Rich,
Cohen Ezra Eddy Wyssam
Publication year - 2011
Publication title -
head and neck
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.012
H-Index - 127
eISSN - 1097-0347
pISSN - 1043-3074
DOI - 10.1002/hed.21701
Subject(s) - pi3k/akt/mtor pathway , protein kinase b , sirolimus , pharmacology , cancer research , carcinogenesis , cell growth , biology , medicine , signal transduction , cancer , microbiology and biotechnology , biochemistry
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. © 2011 Wiley Periodicals, Inc. Head Neck, 2011