FGF-2 Autocrine Signaling in Lung Cancer

描述（由申请人提供）：自分泌生长因子信号，通常通过受体酪氨酸激酶（rtk），是癌细胞的标志。虽然EGF受体（EGFR）和EGF配体家族被认为是人类非小细胞肺癌（NSCLC）的主要自分泌途径，但只有10-20%的患者对EGFR酪氨酸激酶抑制剂（TKI）、吉非替尼和埃洛替尼表现出临床反应。因此，与已知的非小细胞肺癌的异质性一致，EGFR可能不是唯一介导肺癌自分泌生长的RTK。重要的是，我们发现成纤维细胞生长因子2 （FGF2）和FGF受体（fgfr）在NSCLC中经常共表达。此外，FGF2 shrna、显性阴性FGFR1和FGFR TKI （RO4383596）选择性地抑制共表达FGF2和FGFR的NSCLC细胞系的生长。相比之下，缺乏FGF2表达的细胞系对RO4383596耐药，对吉非替尼敏感。其他NSCLC细胞对FGFR和EGFR TKIs的组合表现出加性反应，这意味着双重EGFR和FGFR自分泌输入。最后，我们的初步数据支持FGFR和EGFR环在诱导上皮-间质转化（EMT）中起主导作用，EMT是肿瘤进展和转移的关键程序。总之，我们的研究结果支持了一个假设，即FGF2和fgfr组成了一个自分泌途径，在非小细胞肺癌中作为EGFR自分泌循环的辅助手段来驱动EMT程序。为了验证这一假设，我们将完成这些具体目标。目的1：确定FGF2和FGFR共表达是否有助于NSCLC细胞转化生长。目的2：通过ERK MAP激酶检测FGFR和EGFR自分泌信号在非小细胞肺癌EMT调控中的作用。目的3：确定FGFR自分泌环在人类肺癌进展过程中何时出现，并探索FGF2和FGFR共表达与患者对EGFR TKIs耐药的关系。生长因子受体介导特定肿瘤的转化生长是有吸引力的治疗靶点。在非小细胞肺癌中，EGFR抑制剂已经被应用，但仅取得有限的成功。我们的初步研究表明，许多NSCLC细胞使用FGFR自分泌信号，无论是单独还是与EGFR信号联合，FGFR和EGFR抑制剂对转化生长的加性抑制证明了这一点。因此，在非小细胞肺癌中建立FGF2和特异性fgfr作为共显性自分泌信号通路的组成部分是一个重大问题，对肺癌治疗有很大的潜在影响。

DESCRIPTION (provided by applicant): Autocrine growth factor signaling, often through receptor tyrosine kinases (RTKs), is a hallmark of cancer cells. While EGF receptors (EGFRs) and the EGF family of ligands were thought to constitute a dominant autocrine pathway in human non-small cell lung cancer (NSCLC), only 10-20% of patients exhibit a clinical response to the EGFR tyrosine kinase inhibitors (TKI), gefitinib and erlotinib. Thus, consistent with the known heterogeneity of NSCLC, EGFR is likely not the only RTK mediating autocrine growth in lung cancer. Importantly, we show that fibroblast growth factor 2 (FGF2) and FGF receptors (FGFRs) are frequently co-expressed in NSCLC. Moreover, FGF2 shRNAs, dominant-negative FGFR1 and a FGFR TKI (RO4383596) selectively reduce growth of NSCLC cell lines that co-express FGF2 and FGFRs. By contrast, cell lines lacking FGF2 expression are resistant to RO4383596 and sensitive to gefitinib. Other NSCLC cells exhibit an additive response to combinations of FGFR and EGFR TKIs, implying dual EGFR and FGFR autocrine inputs. Finally, our preliminary data support a dominant role for FGFR and EGFR loops in the induction of epithelial-mesenchymal transition (EMT), a program critical to tumor progression and metastasis. Together, our findings support a hypothesis that FGF2 and FGFRs comprise an autocrine pathway that functions in NSCLC as an auxiliary to EGFR autocrine loops to drive an EMT program. To test this hypothesis, we will complete these specific aims. Aim 1: Define whether FGF2 and FGFR co-expression contributes to NSCLC cell transformed growth. Aim 2: Test the role of FGFR and EGFR autocrine signaling through the ERK MAP kinases in the regulation of EMT in NSCLC. Aim 3: Define when FGFR autocrine loops arise during human lung cancer progression and explore the association of FGF2 and FGFR co-expression with resistance to EGFR TKIs in patients. Growth factor receptors mediating transformed growth of specific tumors represent attractive therapeutic targets. In NSCLC, EGFR inhibitors have already been deployed, but with only limited success. Our preliminary studies indicate that many NSCLC cells employ FGFR autocrine signaling, either alone or in combination with EGFR signaling, as evidenced by additive inhibition of transformed growth by FGFR and EGFR inhibitors. Therefore, establishing FGF2 and specific FGFRs as components of a co-dominant autocrine signal pathway in NSCLC represents a significant problem with a high potential for impact on lung cancer treatment.