Department of Craniofacial Biology, University of Colorado at Denver, Aurora, Colorado, United States of America.
PLoS One. 2010 Nov 29;5(11):e14117. doi: 10.1371/journal.pone.0014117.
Despite initial and sometimes dramatic responses of specific NSCLC tumors to EGFR TKIs, nearly all will develop resistance and relapse. Gene expression analysis of NSCLC cell lines treated with the EGFR TKI, gefitinib, revealed increased levels of FGFR2 and FGFR3 mRNA. Analysis of gefitinib action on a larger panel of NSCLC cell lines verified that FGFR2 and FGFR3 expression is increased at the mRNA and protein level in NSCLC cell lines in which the EGFR is dominant for growth signaling, but not in cell lines where EGFR signaling is absent. A luciferase reporter containing 2.5 kilobases of fgfr2 5' flanking sequence was activated after gefitinib treatment, indicating transcriptional regulation as a contributing mechanism controlling increased FGFR2 expression. Induction of FGFR2 and FGFR3 protein as well as fgfr2-luc activity was also observed with Erbitux, an EGFR-specific monoclonal antibody. Moreover, inhibitors of c-Src and MEK stimulated fgfr2-luc activity to a similar degree as gefitinib, suggesting that these pathways may mediate EGFR-dependent repression of FGFR2 and FGFR3. Importantly, our studies demonstrate that EGFR TKI-induced FGFR2 and FGFR3 are capable of mediating FGF2 and FGF7 stimulated ERK activation as well as FGF-stimulated transformed growth in the setting of EGFR TKIs. In conclusion, this study highlights EGFR TKI-induced FGFR2 and FGFR3 signaling as a novel and rapid mechanism of acquired resistance to EGFR TKIs and suggests that treatment of NSCLC patients with combinations of EGFR and FGFR specific TKIs may be a strategy to enhance efficacy of single EGFR inhibitors.
尽管非小细胞肺癌 (NSCLC) 肿瘤的特定肿瘤对 EGFR TKI 最初有反应，有时甚至是戏剧性的，但几乎所有肿瘤都会产生耐药性并复发。用 EGFR TKI 吉非替尼处理 NSCLC 细胞系的基因表达分析显示 FGFR2 和 FGFR3 mRNA 水平增加。对更大的 NSCLC 细胞系进行的吉非替尼作用分析证实，在 EGFR 对生长信号起主导作用的 NSCLC 细胞系中，FGFR2 和 FGFR3 的表达在 mRNA 和蛋白质水平上增加，但在 EGFR 信号不存在的细胞系中则没有。含有 2.5kb fgfr2 5'侧翼序列的荧光素酶报告基因在吉非替尼处理后被激活，表明转录调控是控制 FGFR2 表达增加的一种机制。用 EGFR 特异性单克隆抗体 Erbitux 也观察到 FGFR2 和 FGFR3 蛋白以及 fgfr2-luc 活性的诱导。此外，c-Src 和 MEK 的抑制剂刺激 fgfr2-luc 活性的程度与吉非替尼相似，表明这些途径可能介导 EGFR 依赖性 FGFR2 和 FGFR3 抑制。重要的是，我们的研究表明，EGFR TKI 诱导的 FGFR2 和 FGFR3 能够介导 FGF2 和 FGF7 刺激的 ERK 激活以及在 EGFR TKI 环境下的 FGF 刺激的转化生长。总之，这项研究强调了 EGFR TKI 诱导的 FGFR2 和 FGFR3 信号是对 EGFR TKI 获得性耐药的一种新的快速机制，并表明用 EGFR 和 FGFR 特异性 TKI 联合治疗 NSCLC 患者可能是增强单 EGFR 抑制剂疗效的一种策略。
