PURPOSE: Acquired resistance to erlotinib in patients with EGFR-mutant non-small 
cell lung cancer can result from aberrant activation of alternative receptor 
tyrosine kinases, such as the HGF-driven c-MET receptor. We sought to determine 
whether inhibition of AKT signaling could augment erlotinib activity and 
abrogate HGF-mediated resistance.
METHODS: The effects of MK-2206, a selective AKT inhibitor, were evaluated in 
combination with erlotinib on a large panel of 13 lung cancer cell lines 
containing different EGFR or KRAS abnormalities. The activity of the combination 
was assessed using proliferation assays, flow cytometry and immunoblotting. The 
MEK inhibitor PD0325901 was used to determine the role of the MAP kinase pathway 
in erlotinib resistance.
RESULTS: The combination of MK-2206 and erlotinib resulted in synergistic growth 
inhibition independent of EGFR mutation status. In cell lines where HGF blocked 
the anti-proliferative and cytotoxic effects of erlotinib, MK-2206 could restore 
cell cycle arrest, but MEK inhibition was required for erlotinib-dependent 
apoptosis. Both AKT and MEK inhibition contributed to cell death independent of 
erlotinib in the T790M-containing H1975 and the EGFR-WT cell lines tested.
CONCLUSIONS: These findings illustrate the potential advantages and challenges 
of combined signal transduction inhibition as a generalized strategy to 
circumvent acquired erlotinib resistance.