AZD6244 and
MK2206 are targeted small-molecule drugs that inhibit
MEK and AKT respectively. The efficacy of this combination in
lung cancer is unknown. Our previous work showed the importance of activated AKT in mediating resistance of
non-small cell lung cancer (NSCLC) to
AZD6244. Thus we hypothesized that dual inhibition of both downstream
MEK and AKT pathways would induce synergistic antitumor activity. In this study, we evaluated the efficacy of
AZD6244 and
MK2206 individually on a large panel of
lung cancer cell lines. Then, we treated 28 human
lung cancer cell lines with a combination of
AZD6244 and
MK2206 at clinically applicable
drug molar ratios. The AZD6244-MK2206 combination
therapy resulted in a synergistic effect on inhibition of
lung cancer cell growth compared to the results of single
drug treatment alone.
MK2206 enhanced AZD6244-induced Bim overexpression and apoptosis in A549 and H157 cells. When we tested the combination of
AZD6244 and
MK2206 at ratios of 8∶1, 4∶1, 2∶1, and 1∶8, we found that the synergistic effect of the combination
therapy was ratio-dependent. At ratios of 8∶1, 4∶1, and 2∶1, the
drug combination consistently demonstrated synergy, whereas decreasing the ratio to 1∶8 resulted in a loss of synergy and produced an additive or antagonistic effect in most cell lines. Furthermore, the AZD6244-MK2206 combination
therapy showed synergy in the suppression of A549 and H157 xenograft
tumor growth and increased mean animal survival time. The AZD6244-MK2206 combination
therapy resulted in effective inhibition of both p-ERK and p-AKT expression in
tumor tissue. In addition, a significant increase of apoptosis was detected in
tumor tissue from mice treated with AZD6244-MK2206 compared with that from the single agent treated mice. Our study suggests that the combination of
AZD6244 and
MK2206 has a significant synergistic effect on
tumor growth in vitro and in vivo and leads to increased survival rates in mice bearing highly aggressive human lung
tumors.