To select the appropriate patients for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), it is important to gain a better understanding of the intracellular pathways leading to EGFR-TKI resistance, which is a common problem in patients with lung cancer. We recently reported that mutantKRASadenocarcinoma is resistant to gefitinib as a result of amphiregulin and insulin-like growth factor-1 receptor overexpression. This resistance leads to inhibition of Ku70 acetylation, thus enhancing the BAX/Ku70 interaction and preventing apoptosis. Here, we determined the intracellular pathways involved in gefitinib resistance in lung cancers and explored the impact of their inhibition. We analyzed the activation of the phosphatidyl inositol-3-kinase (PI3K)/AKT pathway and the mitogen-activated protein kinase/extracellular-signal regulated kinase (MAPK/ERK) pathway in lung tumors. The activation of AKT was associated with disease progression in tumors with wild-typeEGFRfrom patients treated with gefitinib (phase II clinical trial IFCT0401). The administration of IGF1R-TKI or amphiregulin-directed shRNA decreased AKT signaling and restored gefitinib sensitivity in mutantKRAScells. The combination of PI3K/AKT inhibition with gefitinib restored apoptosisviaKu70 downregulation and BAX release from Ku70. Deacetylase inhibitors, which decreased the BAX/Ku70 interaction, inhibited AKT signaling and induced gefitinib-dependent apoptosis. The PI3K/AKT pathway is thus a major pathway contributing to gefitinib resistance in lung tumors withKRASmutation, through the regulation of the BAX/Ku70 interaction. This finding suggests that combined treatments could improve the outcomes for this subset of lung cancer patients, who have a poor prognosis.What's new?
EGFR is frequently overexpressed in non-small cell lungcancers (NSCLCs) and is associated with poor prognosis. While therapies targeting the tyrosine kinase activity of EGFR (EGFR-TKIs, such as gefitinib) are highly effective for the treatment of EGFR mutated NSCLC, limited response rates are observed in EGFR wild-type NSCLC. Here the authors found that the PI3K/AKT pathway contributes to gefitinib resistance in mutantKRAS adenocarcinoma by a deacetylase-dependent mechanism. They showed for the first time that the PI3K/AKT pathway induces survival of wild-type EGFR NSCLCs withKRASmutations, suggesting a new therapeutic target for treating this subset of lung cancer patients.