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Review
. 2009 Aug-Oct;12(4-5):95-102.
doi: 10.1016/j.drup.2009.05.001. Epub 2009 Jun 4.

The fibroblast growth factor receptor signaling pathway as a mediator of intrinsic resistance to EGFR-specific tyrosine kinase inhibitors in non-small cell lung cancer

Scott A Kono  1 , Marianne E Marshall, Kathryn E Ware, Lynn E Heasley
Affiliations
Review

The fibroblast growth factor receptor signaling pathway as a mediator of intrinsic resistance to EGFR-specific tyrosine kinase inhibitors in non-small cell lung cancer

Scott A Kono et al. Drug Resist Updat. 2009 Aug-Oct.

Abstract

The EGFR has been targeted through the development of selective tyrosine kinase inhibitors (TKIs) that have proven effective in a subset of non-small cell lung cancer (NSCLC) patients, many bearing gain-of-function EGFR mutations or egfr gene amplification. However, the majority ( approximately 80-90%) of NSCLC patients do not respond to EGFR-specific TKIs and a high rate of acquired resistance to these therapeutics is observed in those that do respond. Thus, EGFR-specific TKIs will not, as single agents, make a high impact on overall lung cancer survival. A number of studies support the activities of other receptor tyrosine kinase pathways including cMet, IGF-1R and FGFRs as mechanisms for both intrinsic and acquired resistance to EGFR TKIs. While the role of cMet and IGF-1R signaling systems as mechanisms of resistance to EGFR TKIs has been widely reviewed in recent years, the potential role of FGFR-dependent signaling as a mechanism for EGFR TKI resistance has more recently emerged and will be highlighted herein. Due to the high degree of homology of FGFRs with VEGFRs and PDGFRs, FGFR-active TKIs already exist via development of VEGFR-targeted TKIs as angiogenesis inhibitors. Thus, these agents could be rapidly advanced into clinical investigations as FGFR inhibitors, either alone or in combination with TKIs selective for EGFR, cMet or IGF-1R as a means to expand the spectrum of NSCLC patients that can be effectively targeted with TKI-directed therapies.

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Figures

Figure 1
Figure 1. Frequencies of intrinsic resistance to EGFR-specific TKIs relative to sensitivity/acquired resistance in NSCLC
The diagram indicates the relative frequencies of EGFR TKI sensitivity (10–20% in the United States) versus intrinsic resistance (80–90%). Mutation of K-Ras occurs in ~10–30% of adenocarcinomas (but rarely in squamous and large cell carcinoma) and accounts for a known resistance mechanism to EGFR TKIs (Herbst et al., 2008). We hypothesize that autocrine signaling through EGFR-independent receptor tyrosine kinases functions as a mechanism of intrinsic resistance to EGFR TKIs in NSCLC not bearing EGFR or K-Ras mutations.
Figure 2
Figure 2. Autocrine and paracrine growth loops that may contribute to growth and transformation in NSCLC independent of EGFR
The literature (see accompanying text) supports the involvement of cMet, IGF-1R and FGFR receptor tyrosine kinases in the autocrine and paracrine-stimulated growth of NSCLC, thereby conferring intrinsic resistance to EGFR TKIs. In addition to autocrine signaling through EGFR via expression and release of distinct EGF family ligands (TGFα, amphiregulin (AREG), epiregulin (EREG)), the asterisk indicates the presence of activating somatic mutations that occur in EGFR.
Figure 3
Figure 3. Specific FGFs and FGFRs comprise an autocrine growth loop in NSCLC cell lines
While adenocarcinoma is the dominant NSCLC histology sensitive to EGFR TKIs (Herbst et al., 2008), studies with NSCLC cell lines indicate more frequent autocrine signaling in squamous and large cell carcinoma-derived cells through FGF2, FGF9, FGFR1-IIIc and FGFR2-IIIc (Marek et al., 2009; Thomson et al., 2008). Importantly, the homology of FGFRs with VEGFRs and PDGFRs results in frequent activity of VEGFR-targeted TKIs on FGFRs as well (see Table 1). Thus, TKIs in this class target multiple RTKs including VEGFRs, PDGFRs and FGFRs.
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References

    1. Ankrapp DP, Bevan DR. Insulin-like growth factor-I and human lung fibroblast-derived insulin-like growth factor-I stimulate the proliferation of human lung carcinoma cells in vitro. Cancer Res. 1993;53:3399–3404. - PubMed
    1. Bean J, Brennan C, Shih JY, Riely G, Viale A, Wang L, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci (USA) 2007;104:20932–20937. - PMC - PubMed
    1. Behrens C, Lin HY, Lee JJ, Raso MG, Hong WK, Wistuba II, et al. Immunohistochemical expression of basic fibroblast growth factor and fibroblast growth factor receptors 1 and 2 in the pathogenesis of lung cancer. Clin Cancer Res. 2008;14:6014–6022. - PMC - PubMed
    1. Berger W, Setinek U, Mohr T, Kindas-Mugge I, Vetterlein M, Dekan G, et al. Evidence for a role of FGF-2 and FGF receptors in the proliferation of non-small cell lung cancer cells. Int J Cancer. 1999;83:415–423. - PubMed
    1. Bhide RS, Cai ZW, Zhang YZ, Qian L, Wei D, Barbosa S, et al. Discovery and preclinical studies of (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5- methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan- 2-ol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor. J Med Chem. 2006;49:2143–2146. - PubMed

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