Effect of simvastatin on the resistance to EGFR tyrosine kinase inhibitors in a non-small cell lung cancer with the T790M mutation of EGFR.

Although non-small cell lung cancer (NSCLC) tumors with activating mutations in the epidermal growth factor receptor (EGFR) are highly responsive to EGFR tyrosine kinase inhibitors (TKIs) including gefitinib and erlotinib, development of acquired resistance is almost inevitable. Statins show antitumor activity, but it is unknown whether they can reverse EGFR-TKIs resistance in NSCLC with the T790M mutation of EGFR. This study investigated overcoming resistance to EGFR-TKI using simvastatin. We demonstrated that addition of simvastatin to gefitinib enhanced caspase-dependent apoptosis in T790M mutant NSCLC cells. Simvastatin also strongly inhibited AKT activation, leading to suppression of β-catenin activity and the expression of its targets, survivin and cyclin D1. Both insulin treatment and AKT overexpression markedly increased p-β-catenin and survivin levels, even in the presence of gefitinib and simvastatin. However, inhibition of AKT by siRNA or LY294002 treatment decreased p-β-catenin and survivin levels. To determine the role of survivin in simvastatin-induced apoptosis of gefitinib-resistant NSCLC, we showed that the proportion of apoptotic cells following treatment with survivin siRNA and the gefitinib-simvastatin combination was greater than the theoretical additive effects, whereas survivin up-regulation could confer protection against gefitinib and simvastatin-induced apoptosis. Similar results were obtained in erlotinib and simvastatin-treated HCC827/ER cells. These findings suggest that survivin is a key molecule that renders T790M mutant NSCLC cells resistant to apoptosis induced by EGFR-TKIs and simvastatin. Overall, these data indicate that simvastatin may overcome EGFR-TKI resistance in T790M mutant NSCLCs via an AKT/β-catenin signaling-dependent down-regulation of survivin and apoptosis induction.

Hwang KE ，Kwon SJ ，Kim YS ，Park DS ，Kim BR ，Yoon KH ，Jeong ET ，Kim HR ... -  《-》

Knockdown of the Bcl-2 gene increases sensitivity to EGFR tyrosine kinase inhibitors in the H1975 lung cancer cell line harboring T790M mutation.

Zou M ，Xia S ，Zhuang L ，Han N ，Chu Q ，Chao T ，Peng P ，Chen Y ，Gui Q ，Yu S ... -  《-》

Implication of the insulin-like growth factor-IR pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib.

Morgillo F ，Kim WY ，Kim ES ，Ciardiello F ，Hong WK ，Lee HY ... -  《CLINICAL CANCER RESEARCH》

Antitumor activity of combination treatment with gefitinib and docetaxel in EGFR-TKI-sensitive, primary resistant and acquired resistant human non-small cell lung cancer cells.

Wu M ，Yuan Y ，Pan YY ，Zhang Y ... -  《-》

Combined inhibition of IGFR enhances the effects of gefitinib in H1650: a lung cancer cell line with EGFR mutation and primary resistance to EGFR-TK inhibitors.

Choi YJ ，Rho JK ，Jeon BS ，Choi SJ ，Park SC ，Lee SS ，Kim HR ，Kim CH ，Lee JC ... -  《-》