FGF-2 Autocrine Signaling in Lung Cancer

描述(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。虽然表皮生长因子受体(EGFR)和EGF家族配体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)、吉非替尼和厄洛替尼有临床反应。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)和成纤维细胞生长因子受体(FGFRs)在非小细胞肺癌中经常共表达。此外，FGF2 shRNA、显性负FGFR1和FGFR TKI(RO4383596)选择性地抑制共表达FGF2和FGFRs的非小细胞肺癌细胞系的生长。相反，缺乏FGF2表达的细胞株对RO4383596耐药，而对吉非替尼敏感。其他NSCLC细胞对FGFR和EGFR TKI的组合表现出相加的反应，这意味着双重的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-间充质转化(EMT)中起主导作用，EMT是肿瘤进展和转移的关键程序。总之，我们的发现支持这样一种假设，即FGF2和FGFRs组成了一个自分泌途径，在非小细胞肺癌中作为EGFR自分泌循环的辅助来驱动EMT程序。为了检验这一假设，我们将完成这些具体目标。目的1：探讨FGF2和FGFR共表达对非小细胞肺癌细胞转化生长的影响。目的：检测FGFR和EGFR自分泌信号通过ERK MAP激酶在非小细胞肺癌EMT调控中的作用。目的3：明确肺癌进展过程中FGFR自分泌环路何时出现，并探讨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，已经部署了EGFR抑制剂，但仅取得了有限的成功。我们的初步研究表明，许多NSCLC细胞使用FGFR自分泌信号，要么单独使用，要么与EGFR信号联合使用，FGFR和EGFR抑制剂对转化生长的相加抑制证明了这一点。因此，在非小细胞肺癌中建立FGF2和特定的FGFRs作为共支配的自分泌信号通路的组成部分是一个重要的问题，具有很高的潜在影响肺癌治疗。

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.