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.
|Marek, Lindsay A; Hinz, Trista K; von Mässenhausen, Anne et al. (2014) Nonamplified FGFR1 is a growth driver in malignant pleural mesothelioma. Mol Cancer Res 12:1460-9|
|Wynes, Murry W; Hinz, Trista K; Gao, Dexiang et al. (2014) FGFR1 mRNA and protein expression, not gene copy number, predict FGFR TKI sensitivity across all lung cancer histologies. Clin Cancer Res 20:3299-309|
|Kim, Jihye; Vasu, Vihas T; Mishra, Rangnath et al. (2014) Bioinformatics-driven discovery of rational combination for overcoming EGFR-mutant lung cancer resistance to EGFR therapy. Bioinformatics 30:2393-8|
|Linger, R M A; Cohen, R A; Cummings, C T et al. (2013) Mer or Axl receptor tyrosine kinase inhibition promotes apoptosis, blocks growth and enhances chemosensitivity of human non-small cell lung cancer. Oncogene 32:3420-31|
|Ware, K E; Hinz, T K; Kleczko, E et al. (2013) A mechanism of resistance to gefitinib mediated by cellular reprogramming and the acquisition of an FGF2-FGFR1 autocrine growth loop. Oncogenesis 2:e39|
|Singleton, Katherine R; Kim, Jihye; Hinz, Trista K et al. (2013) A receptor tyrosine kinase network composed of fibroblast growth factor receptors, epidermal growth factor receptor, v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, and hepatocyte growth factor receptor drives growth and survival of head and ne Mol Pharmacol 83:882-93|
|Kono, S A; Heasley, L E; Doebele, R C et al. (2012) Adding to the mix: fibroblast growth factor and platelet-derived growth factor receptor pathways as targets in non-small cell lung cancer. Curr Cancer Drug Targets 12:107-23|
|Marshall, Marianne E; Hinz, Trista K; Kono, Scott A et al. (2011) Fibroblast growth factor receptors are components of autocrine signaling networks in head and neck squamous cell carcinoma cells. Clin Cancer Res 17:5016-25|
|Ware, Kathryn E; Marshall, Marianne E; Heasley, Lydia R et al. (2010) Rapidly acquired resistance to EGFR tyrosine kinase inhibitors in NSCLC cell lines through de-repression of FGFR2 and FGFR3 expression. PLoS One 5:e14117|
|Marek, Lindsay; Ware, Kathryn E; Fritzsche, Alexa et al. (2009) Fibroblast growth factor (FGF) and FGF receptor-mediated autocrine signaling in non-small-cell lung cancer cells. Mol Pharmacol 75:196-207|
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