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

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 inhibi- tor with nanomolar inhibitory concentrations for Akt and protein kinase C (PKC). Moreover, Akt and PKC inhibitors have dem- onstrated 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 puta- tive 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 path- ways in SCCHN and has efficacy in preclinical models. V C 2011 Wiley Periodicals, Inc. Head Neck 33: 1774-1782, 2011