Clinical resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment has been observed in lung cancer. The antidiabetic drug metformin has shown significant inhibitory and proapoptotic effects in several cancer models alone and in combination with chemotherapeutic drugs. Morgillo and colleagues assessed the effects of the selective EGFR tyrosine kinase inhibitor gefitinib (Iressa) and metformin in a panel of non–small cell lung cancer (NSCLC) cell lines.
The combination of metformin with gefitinib induced a strong antiproliferative and proapoptotic effect in NSCLC cell lines with wild-type LKB1. Treatment with metformin alone induced activation and phosphorylation of MAPK through increased CRAF:BRAF heterodimerization. The inhibition of EGFR phosphorylation and downstream signaling with the addition of gefitinib prevented this effect and resulted in a strong apoptotic effect in vitro and in vivo.
The investigators concluded, “Metformin and gefitinib are synergistic in LKB1 wild-type NSCLC cells. However, further studies are required to investigate better the effect of metformin action on the RAS/RAF/MAPK pathway and the best context in which to use metformin in combination with molecular targeted agents.” ■
Morgillo F, et al: Clin Cancer Res. May 21, 2013 (early release online).