nsclc逆转耐药之辛伐他汀

Effect of simvastatin on the resistance to EGFR tyrosine kinase inhibitors in a non-small cell lung cancer with the T790M mutation of EGFR.
吉非替尼加辛伐他汀加强t790m中附属凋亡蛋白酶的凋亡。辛伐他汀也强抑制akt活性，导致连环蛋白活性及其靶向生存蛋白和周期蛋白1的表达被抑制。通过 siRNA或LY294002治疗抑制akt，降低了p-β-catenin 和 生存蛋白水平.根据凋亡细胞比例发现生存蛋白siRNA治疗及吉非替尼和辛伐他汀联合治疗效果明显大于1+1=2.然而生存蛋白的上调抗联合诱导的凋亡。类似的结果在厄洛替尼联合辛伐他汀治疗的HCC827/ER细胞系中出现。这些发现建议生存蛋白是应该关键分子使得t790m突变的肿瘤细胞对tki和辛伐他汀耐药。总之，辛伐他汀通过AKT/β-catenin通路下调生存蛋白和诱导凋亡克服tki的耐药。
Abstract
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.
Copyright © 2014 Elsevier Inc. All rights reserved.
KEYWORDS: EGFR tyrosine kinase inhibitors; Lung cancer; Resistance; Simvastatin
PMID:24631288

http://www.ncbi.nlm.nih.gov/pubmed/24631288