EGFR tyrosine kinase inhibitors (TKIs) are clinically useful agents for the treatment of NSCLC, yet resistance ultimately develops. In an effort to develop strategies to combat resistance and prolong patient benefit, EGFR TKIs were combined with the Akt inhibitor triciribine in a panel of EGFR TKI-resistant NSCLC cell lines. The combination synergistically reduced proliferation in cells that expressed a variety of resistance mechanisms, including intrinsic EGFR T790M mutations, K-Ras mutations, and Met amplification. The combination of erlotinib and triciribine significantly increased apoptosis in H1975 and H1650 cells. It also decreased the phosphorylation of Akt and PRAS40, C-Raf, MEK, and ERK to a greater extent than either drug alone. Unbiased analysis using reverse phase lysate arrays confirmed decreased activation of PI3K/Akt pathway components as well as ERK. The effect of the combination appeared to depend on downregulation of Akt, since a constitutively active form of Akt abrogated the decreased proliferation and increase in cell death caused by the combination. In vivo, the combination inhibited the growth of H1975 xenografts to a greater extent than either drug alone. When tested in an invariably progressive, transgenic model of EGFR-driven lung tumorigenesis (EGFR L858R/T790M), the combination did not cause regression of tumors but stabilized disease in approximately 80% of mice. We conclude the combination of triciribine with EGFR TKIs is promising and should be explored clinically, and that combining inhibitors of the PI3K/Akt pathway with EGFR TKIs may be a useful strategy to overcome EGFR TKI resistance.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 624.