Cancer Science Institute, National University of Singapore, Singapore, Singapore.
Cancer Chemother Pharmacol. 2013 May;71(5):1325-34. doi: 10.1007/s00280-013-2132-y. Epub 2013 Mar 21.
Sensitivity to a tyrosine kinase inhibitor (TKI) is correlated with the presence of somatic mutations that affect the kinase domain of epidermal growth factor receptor (EGFR). Development of resistance to TKI is a major therapeutic problem in non-small cell lung cancer (NSCLC). Aim of this study is to identify agents that can overcome TKI resistance in NSCLC.
We used a carefully selected panel of 12 NSCLC cell lines to address this clinical problem. Initially, the cell lines were treated with a variety of 10 compounds. Cellular proliferation was measured via MTT assay. We then focused on the gefitinib-resistant, EGFR mutant cell lines [H1650: exon 19 and PTEN mutations; and H1975: exons 20 (T790M) and 21 (L858R)] to identify agents that could overcome TKI resistance.
Both 17-DMAG (Hsp90 inhibitor) and belinostat (histone deacetylase inhibitor, HDACi) effectively decreased the growth of almost all NSCLC lines. Also, belinostat markedly decreased the expression of EGFR and phospho-Akt in the cells. Combination of 17-DMAG and belinostat synergistically inhibited in vitro proliferation of these cells. Furthermore, both agents and their combination almost completely prevented TKI-resistant tumor formation (EGFR T790M mutation) in a xenograft model.
These results suggest that the combination of 17-DMAG and belinostat should be examined in a clinical trial for TKI-resistant NSCLC cell.
对酪氨酸激酶抑制剂（TKI）的敏感性与影响表皮生长因子受体（EGFR）激酶结构域的体细胞突变的存在相关。TKI 耐药的发展是治疗非小细胞肺癌（NSCLC）的一个主要问题。本研究旨在确定能够克服 NSCLC 中 TKI 耐药的药物。
我们使用了精心挑选的 12 种 NSCLC 细胞系来解决这个临床问题。最初，用各种 10 种化合物处理细胞系。通过 MTT 测定法测量细胞增殖。然后，我们专注于吉非替尼耐药的 EGFR 突变细胞系[H1650：外显子 19 和 PTEN 突变；和 H1975：外显子 20（T790M）和 21（L858R）]，以确定能够克服 TKI 耐药的药物。
17-DMAG（Hsp90 抑制剂）和 belinostat（组蛋白去乙酰化酶抑制剂，HDACi）均有效地降低了几乎所有 NSCLC 细胞系的生长。此外，belinostat 显著降低了细胞中 EGFR 和磷酸化 Akt 的表达。17-DMAG 和 belinostat 的联合显著抑制了这些细胞的体外增殖。此外，这两种药物及其联合几乎完全阻止了异种移植模型中 TKI 耐药肿瘤（EGFR T790M 突变）的形成。
这些结果表明，17-DMAG 和 belinostat 的联合应该在 TKI 耐药 NSCLC 细胞的临床试验中进行检查。
