Fibroblast growth factor receptor-mediated signals contribute to the malignant phenotype of non-small cell lung cancer cells: therapeutic implications and synergism with epidermal growth factor receptor inhibition

Abstract

Fibroblast growth factors (FGF) and their high-affinity receptors (FGFR) represent an extensive cellular growth and survival system. Aim of this study was to evaluate the contribution of FGF/FGFR-mediated signals to the malignant growth of non-small cell lung cancer (NSCLC) and to assess their potential as targets for therapeutic interventions. Multiple FGFR mRNA splice variants were coexpressed in NSCLC cells (n = 16) with predominance of FGFR1. Accordingly, both expression of a dominantnegative FGFR1 (dnFGFR1) IIIc-green fluorescent protein fusion protein and application of FGFR small-molecule inhibitors (SU5402 and PD166866) significantly reduced growth, survival, clonogenicity, and migratory potential of the majority of NSCLC cell lines. Moreover, dnFGFR1 expression completely blocked or at least significantly attenuated s.c. tumor formation of NSCLC cells in severe combined immunodeficient mice. Xenograft tumors expressing dnFGFR1 exhibited significantly reduced size and mitosis rate, enhanced cell death, and decreased tissue invasion. When FGFR inhibitors were combined with chemotherapy, antagonistic to synergistic in vitro anticancer activities were obtained depending on the application schedule. In contrast, simultaneous blockage of FGFR-and epidermal growth factor receptor-mediated signals exerted synergistic effects. In summary, FGFRmediated signals in cooperation with those transmitted by epidermal growth factor receptor are involved in growth and survival of human NSCLC cells and should be considered as targets for combined therapeutic approaches.

Phase I/II and Pharmacodynamic Study of Dovitinib (TKI258), an Inhibitor of Fibroblast Growth Factor Receptors and VEGF Receptors, in Patients with Advanced Melanoma

“…Because dovitinib is an inhibitor of FGFRs and VEGFRs, in contrast with other tyrosine kinase inhibitors (e.g., sorafenib and sunitinib), it may be beneficial in FGF-activated cancers. These include breast cancers (due to FGFR1 amplification), bladder cancer (due to FGFR3 mutations), multiple myeloma (due to FGFR3 overexpression), and endometrial cancers (due to FGFR2 mutations), for which dysregulation of the FGFR pathway is important in tumor survival (38)(39)(40)(41)(42)(43)(44)(45)(46). FGFR inhibition may also have utility in renal and hepatocellular cancers because the upregulation of FGF signaling seems to play a role in resistance to VEGFR inhibitors (47,48).…”

High-Affinity Internalizing Human scFv-Fc Antibody for Targeting FGFR1-Overexpressing Lung Cancer

“…These diverse ligand-receptor combinations mediate multiple developmental programs during embryogenesis, as well as adult tissue repair and maintenance. Elevated FGFR1 expression and upregulation of FGFR/ FGF signaling apparently lead to cell transformation and lung carcinogenesis (20)(21)(22)(23)(24), and negatively affects the survival of patients (14,25). It has been demonstrated, using cell cultures and xenografted mouse models, that SCC carrying FGFR1 gene amplifications responds effectively to therapy that blocks FGFR1 activity (14,26), revealing the first high-frequency targetable oncogene specific for smoking-associated lung cancer (27).…”

Activation of the FGF2-FGFR1 Autocrine Pathway: A Novel Mechanism of Acquired Resistance to Gefitinib in NSCLC

“…They are also reported to be implicated in tumorigenesis as candidate "driver" oncogenes (19,20). Numerous in vitro studies revealed frequent coexpression of specific FGFs as well as FGFR1 and FGFR2 (17,18,21), and several independent studies showed frequent coexpression of FGF2, FGFR1, and FGFR2 in primary NSCLC specimens (22)(23)(24). Importantly, inhibition of FGFR signaling via dominant-negative FGFR1 (21), FGF2 neutralizing antibodies (17), FGFR-TKI (18), or antisense RNA (18,25) blocked proliferation of tumor growth in NSCLC.…”