Elevated ß-catenin pathway as a novel target for patients with resistance to EGF receptor targeting drugs.

There is a high death rate of lung cancer patients. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in some lung adenocarcinoma patients with EGFR mutations. However, a significant number of patients show primary and acquire resistance to EGFR-TKIs. Although the Akt kinase is commonly activated due to various resistance mechanisms, the key targets of Akt remain unclear. Here, we show that the Akt-ß-catenin pathway may be a common resistance mechanism. We analyzed gene expression profiles of gefitinib-resistant PC9M2 cells that were derived from gefitinib-sensitive lung cancer PC9 cells and do not have known resistance mechanisms including EGFR mutation T790M. We found increased expression of Axin, a ß-catenin target gene, increased phosphorylation of Akt and GSK3, accumulation of ß-catenin in the cytoplasm/nucleus in PC9M2 cells. Both knockdown of ß-catenin and treatment with a ß-catenin inhibitor at least partially restored gefitinib sensitivity to PC9M2 cells. Lung adenocarcinoma tissues derived from gefitinib-resistant patients displayed a tendency to accumulate ß-catenin in the cytoplasm. We provide a rationale for combination therapy that includes targeting of the Akt-ß-catenin pathway to improve the efficacy of EGFR-TKIs.