Binding of human recombinant mutant soluble ectodomain of FGFR2IIIc to c subtype of FGFRs: implications for anticancer activity

Abstract

FGFRs are considered essential targets for cancer therapy. We previously reported that msFGFR2c, a Ser252Trp mutant soluble ectodomain of FGFR2IIIc, inhibited tumor growth by blocking FGF signaling pathway. However, the underlying molecular mechanism is still obscure. In this study, we reported that msFGFR2c but not wild-type soluble ectodomain of FGFR2IIIc (wsFGFR2c) could selectively bind to c subtype of FGFRs in the presence of FGF-2. Thermodynamic analysis demonstrated that msFGFR2c bound to wsFGFR2c in the presence of FGF-2 with a K value of 6.61 × 105 M−1. Molecular dynamics simulations revealed that the mutated residue Trp252 of msFGFR2c preferred a π-π interaction with His254 of wsFGFR2c. Concomitantly, Arg255 of msFGFR2c and Glu250 of wsFGFR2c adjusted their conformations and formed three H-bonds. These two interactions therefore stabilized the final structure of wsFGFR2c and msFGFR2c heterocomplex. In FGFR2IIIc-positive/high FGF-2-secreted BT-549 cells, msFGFR2c significantly inhibited the proliferation and induced apoptosis by the blockage of FGF-2-activated FGFRs phosphorylation, also the growth and angiogenesis of its xenograft tumors implanted in chick embryo chorioallantoic membrane model. While weaker the above inhibitory effects of msFGFR2c were observed on FGFR2IIIc-negative/low FGF-2-secreted MCF-7 and MDA-MB-231 cell lines in vitro and in vivo. Moreover, msFGFR2c significantly inhibited the proliferation of FGFR1IIIc-positive NCI-H1299 lung cancer cells by the suppression of FGF-2-induced FGFR1 activation and suppressed the growth of NCI-H1299 transplanted tumors in nude mice. In sum, msFGFR2c is a potential anti-tumor agent targeting FGFR2c/FGFR1c-positive tumor cells. These findings also provide a molecular basis for msFGFR2c to disrupt the activation of FGF signaling.

Inhibitory effects of msFGFR2c on the epithelial-to-mesenchymal transition of AE2 cells in pulmonary fibrosis

“…Owing to their crucial role in pulmonary fibrosis (Corti et al 1996;Ehrhardt et al 2005;Fujino et al 2011;Liu et al 2016), mouse primary AE2 cells were examined in this study. Here, we found that the addition of fibroblast medium of MRC-5 cells increased N-cadherin and a-SMA levels and decreased E-cadherin levels in AE2 cells (Fig.…”

New developments in the biology of fibroblast growth factors

“…Monoclonal antibodies targeting FGFs and FGFRs, ligand traps (soluble FGFR ligand binding domains), small‐molecule FGFR inhibitors, and aptamers are being developed for the treatment of a variety of genetic, metabolic, and oncologic human diseases (Table 2) (Chioni & Grose, 2021; Grabner et al, 2015; Herbert et al, 2014; Ho et al, 2009; Liu et al, 2016; Ornitz & Itoh, 2015; Ornitz & Legeai‐Mallet, 2017; Presta et al, 2017; Szymczyk et al, 2021; Weaver & Bossaer, 2021). Among them, some medications including Burosumab, Erdafitnib, and Pemigatinib have been approved for therapeutic use by the US Food and Drug Administration (FDA).…”

“…Soluble extracellular domains of FGFR1c, FGFR2b, FGFR2c, and FGFR3c have been developed as ligand trap inhibitors and have been evaluated in vivo (Blackwell et al, 2016; Garcia et al, 2013; Goncalves et al, 2020; Liu et al, 2016; Saint‐Laurent et al, 2018; Tolcher et al, 2016). As an example, mesothelioma and other lung cancers express high levels of FGF2 and FGFR1 (Marek et al, 2014; Wynes et al, 2014).…”

Fibroblast growth factor receptor signalling dysregulation and targeting in breast cancer

“…A complete understanding of the role of FGFR signalling in breast cancer biology and of how FGFR signalling architecture adapts during breast cancer progression [250] or treatment with canonical strategies will then pave the way for discovering or improving novel strategies to benefit breast cancer patients. For instance, the use either of certain FGFs as therapeutics or of more specific ligand-trap molecules and isoform-specific FGFR inhibitors still needs further optimization [2,133,[251][252][253][254].…”