Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan.
Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan.
Lung Cancer. 2017 Feb;104:85-90. doi: 10.1016/j.lungcan.2016.12.012. Epub 2016 Dec 21.
The epithelial to mesenchymal transition (EMT) is associated with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in certain non-small cell lung cancers that harbor EGFR mutations. Because no currently available drugs specifically kill cancer cells via EMT, novel treatment strategies that overcome or prevent EMT are needed. A recent report suggested that dasatinib (an ABL/Src kinase inhibitor) inhibits EMT induced by transforming growth factor (TGF)-beta in lung cancer cells (Wilson et al., 2014). In this study, we analyzed effects of dasatinib on the resistance mechanism in HCC4006 cells, which tend to acquire resistance to EGFR-TKIs via EMT.
Sensitivity to dasatinib in HCC4006 and HCC4006 erlotinib-resistant (ER) cells with an EMT phenotype was analyzed. HCC4006 cells acquired resistance against the combination of erlotinib and dasatinib (HCC4006EDR) following chronic treatment with these drugs. The expression of EMT markers and the resistance mechanism were analyzed.
Short-term or long-term treatment with dasatinib did not reverse EMT in HCC4006ER. In contrast, HCC4006EDR cells maintained an epithelial phenotype, and the mechanism underlying resistance to erlotinib plus dasatinib combination therapy was attributable to a T790M secondary mutation. HCC4006EDR cells, but not HCC4006ER cells, were highly sensitive to a third-generation EGFR-TKI, osimertinib.
Although dasatinib monotherapy did not reverse EMT in HCC4006ER cells, preemptive combination treatment with erlotinib and dasatinib prevented the emergence of acquired resistance via EMT, and led to the emergence of T790M. Our results indicate that preemptive combination therapy may be a promising strategy to prevent the emergence of EMT-mediated resistance.
上皮间质转化（EMT）与某些携带表皮生长因子受体（EGFR）突变的非小细胞肺癌对 EGFR 酪氨酸激酶抑制剂（TKI）获得性耐药有关。由于目前尚无专门通过 EMT 杀死癌细胞的药物，因此需要新的治疗策略来克服或预防 EMT。最近的一份报告表明，达沙替尼（一种 ABL/Src 激酶抑制剂）可抑制 TGF-β诱导的肺癌细胞中的 EMT（Wilson 等人，2014 年）。在这项研究中，我们分析了达沙替尼对 HCC4006 细胞耐药机制的影响，该细胞通过 EMT 倾向于对 EGFR-TKI 产生耐药性。
分析了 HCC4006 和具有 EMT 表型的 HCC4006 厄洛替尼耐药（ER）细胞对达沙替尼的敏感性。这些药物的慢性治疗后，HCC4006 细胞对厄洛替尼和达沙替尼的联合治疗产生了耐药性（HCC4006EDR）。分析了 EMT 标志物的表达和耐药机制。
短期或长期用达沙替尼处理均未逆转 HCC4006ER 中的 EMT。相比之下，HCC4006EDR 细胞保持上皮表型，对厄洛替尼加达沙替尼联合治疗的耐药机制归因于 T790M 继发突变。HCC4006EDR 细胞而非 HCC4006ER 细胞对第三代 EGFR-TKI 奥希替尼高度敏感。
尽管达沙替尼单药治疗不能逆转 HCC4006ER 细胞中的 EMT，但厄洛替尼和达沙替尼的预先联合治疗可防止 EMT 引起的获得性耐药，并导致 T790M 的出现。我们的结果表明，预先联合治疗可能是预防 EMT 介导的耐药性出现的一种有前途的策略。
