Department of Internal Medicine, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
Mol Cancer Res. 2009 Oct;7(10):1736-43. doi: 10.1158/1541-7786.MCR-08-0504. Epub 2009 Oct 6.
The development of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) seems almost inevitable, even in patients with lung cancer that initially respond well to EGFR-TKIs. MET amplification was recently found to be a mechanism of escape from the anticancer effect of EGFR inhibitors. In the present study, we investigated the means whereby MET affects sensitivity to EGFR-TKIs in PC-9 cells. Gefitinib- or erlotinib-resistant sublines were established by exposing the parental PC-9 cell line to chronic, repeated treatments with these drugs. These resistant sublines showed more than 100-fold more resistance to gefitinib and erlotinib and acquired cross-resistance to other EGFR-TKIs. The T790M EGFR mutation was found by pyrosequencing, and this seemed to be the cause of drug resistance. Resistant cells also showed MET activation, although gene amplification was not detected. Furthermore, the induction of MET activity was not found to be associated with sensitivity to EGFR-TKIs. Interestingly, increased passage number without exposure to gefitinib or erlotinib caused MET activation, but this did not affect sensitivity to EGFR-TKIs. In addition, hepatocyte growth factor was found to block the ability of EGFR-TKIs to inhibit MET activation. However, sustained MET activation by hepatocyte growth factor did not modulate the cellular effects of gefitinib or erlotinib. Rather, activated MET enhanced migration and invasion abilities. Summarizing, MET activation may be acquired during cancer cell proliferation and enhances migratory and invasive abilities without affecting cellular sensitivity to EGFR-TKIs. Accordingly, the present study suggests that MET activation caused by factors other than MET gene amplification is not a suitable surrogate marker of resistance to EGFR-TKIs.
表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）耐药的发展似乎几乎是不可避免的，即使是对 EGFR-TKIs 最初反应良好的肺癌患者也是如此。最近发现 MET 扩增是逃避 EGFR 抑制剂抗癌作用的一种机制。在本研究中，我们研究了 MET 影响 PC-9 细胞对 EGFR-TKIs 敏感性的方式。通过对亲本 PC-9 细胞系进行慢性、重复的药物处理，建立了对吉非替尼或厄洛替尼耐药的亚系。这些耐药亚系对吉非替尼和厄洛替尼的耐药性超过 100 倍，并获得了对其他 EGFR-TKIs 的交叉耐药性。通过焦磷酸测序发现了 T790M EGFR 突变，这似乎是耐药的原因。耐药细胞也显示出 MET 激活，尽管未检测到基因扩增。此外，诱导 MET 活性与对 EGFR-TKIs 的敏感性无关。有趣的是，未经吉非替尼或厄洛替尼暴露而增加传代数会导致 MET 激活，但这并不影响对 EGFR-TKIs 的敏感性。此外，还发现肝细胞生长因子可阻断 EGFR-TKIs 抑制 MET 激活的能力。然而，肝细胞生长因子持续激活 MET 并没有调节吉非替尼或厄洛替尼的细胞效应。相反，激活的 MET 增强了迁移和侵袭能力。总之，MET 激活可能在癌细胞增殖过程中获得，并增强迁移和侵袭能力，而不影响对 EGFR-TKIs 的细胞敏感性。因此，本研究表明，除 MET 基因扩增以外的因素引起的 MET 激活不是对 EGFR-TKIs 耐药的合适替代标志物。
