Structural Analysis of the Human Fibroblast Growth Factor Receptor 4 Kinase

Lesca, Elena; Lammens, Alfred; Huber, Robert; Augustin, Martin

doi:10.1016/j.jmb.2014.09.004

Cited by 40 publications

(37 citation statements)

References 54 publications

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“…Crystallographic analysis showed that dovitinib and ponatinib showed no appreciable contact with the P‐loop (Lesca et al . ; Tucker et al . ; Bunney et al .…”

Section: Discussionmentioning

confidence: 99%

“…The reduced affinity of the V561M mutant for PD173074 was caused not only by steric hindrance around the gatekeeper residues, but also by steric clash induced by the structural change around the P-loop region. Crystallographic analysis showed that dovitinib and ponatinib showed no appreciable contact with the Ploop (Lesca et al 2014;Tucker et al 2014;Bunney et al 2015;Klein et al 2015); therefore, the conformational state of the P-loop was considered not to affect the association of these two drugs with FGFR kinases. It has also been reported that dovitinib and ponatinib come into contact with the gatekeeper residue.…”

Section: Discussionmentioning

confidence: 99%

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Biophysical characterization of drug‐resistant mutants of fibroblast growth factor receptor 1

et al. 2016

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Over-expression and aberrant activation of tyrosine kinases occur frequently in human cancers. Various tyrosine kinase inhibitors (TKIs) are under clinical use, but acquisition of resistance to these drugs is a major problem. Here, we studied the interaction between two drug-resistant mutants of fibroblast growth factor receptor 1 (FGFR1), N546K and V561M, and four ATP-competitive inhibitors, ponatinib, dovitinib, PD173074 and BGJ-398. Among these protein-drug systems, the only marked reduction in affinity was that of PD173074 for the V561M mutant. We also examined the interaction of these FGFR1 variants to AMP-PNP, a nonhydrolyzable analogue of ATP, and showed that N546K showed increased affinity for the ATP analogue as compared with the wild type. These findings will help to clarify the mechanism of drug resistance in mutant tyrosine kinases.

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“…Crystallographic analysis showed that dovitinib and ponatinib showed no appreciable contact with the P‐loop (Lesca et al . ; Tucker et al . ; Bunney et al .…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Biophysical characterization of drug‐resistant mutants of fibroblast growth factor receptor 1

et al. 2016

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“…A further challenge is the lack of FGFR3/4‐selective therapies. In first preliminary experiments, we applied (1) ponatinib, a kinase inhibitor of BCR‐ABL, members of the FGFR, platelet‐derived growth factor receptor, and vascular endothelial growth factor receptor families, and (2) NVP‐BGJ398, a selective inhibitor of FGFR1, FGFR2, and FGFR3 . Both compounds reduced dose dependently the number of viable hepatoma/hepatocarcinoma cells and clone formation of the cells (http://onlinelibrary.wiley.com/doi/10.1002/hep.28023/suppinfo).…”

Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor receptor 3 isoforms: Novel therapeutic targets for hepatocellular carcinoma?

et al. 2015

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Fibroblast growth factor receptors (FGFRs) are frequently up-regulated in subsets of hepatocellular carcinoma (HCC). Here, we provide mechanistic insight that FGFR3 splice variants IIIb and IIIc impact considerably on the malignant phenotype of HCC cells. The occurrence of FGFR3 variants was analyzed in human HCC samples. In hepatoma/hepatocarcinoma cell lines, FGFR3 isoforms were overexpressed by lentiviral constructs or down-modulated by small interfering RNA (siRNA; affecting FGFR3-IIIb and -IIIc) or an adenoviral kinase-dead FGFR3-IIIc construct (kdFGFR3). Elevated levels of FGFR3-IIIb and/or -IIIc were found in 53% of HCC cases. FGFR3-IIIb overexpression occurred significantly more often in primary tumors of large (pT2-4) than of small size (pT1). Furthermore, one or both isoforms were enhanced mostly in cases with early tumor infiltration and/or recurrence at the time of surgery or follow-up examinations. In hepatoma/hepatocarcinoma cells, up-regulated FGFR3-IIIb conferred an enhanced capability for proliferation. Both FGFR3-IIIb and FGFR3-IIIc suppressed apoptotic activity, enhanced clonogenic growth, and induced disintegration of the blood/lymph endothelium. The tumorigenicity of cells in severe combined immunodeficiency mice was augmented to a larger degree by variant IIIb than by IIIc. Conversely, siRNA targeting FGFR3 and kdFGFR3 reduced clonogenicity, anchorage-independent growth, and disintegration of the blood/lymph endothelium in vitro. Furthermore, kdFGFR3 strongly attenuated tumor formation in vivo. Conclusions: Deregulated FGFR3 variants exhibit specific effects in the malignant progression of HCC cells. Accordingly, blockade of FGFR3-mediated signaling may be a promising therapeutic approach to antagonize growth and malignant behavior of HCC cells. (HEPATOLOGY 2015;62:1767-1778 H epatocellular carcinoma (HCC), the most frequent primary malignant liver tumor entity, is estimated to be the second-leading cause for cancer mortality worldwide. 1 Owing to the high inherent chemoresistance of this tumor type, standard chemotherapy is insufficient and only 15% of the patients are candidates for surgical resection or liver transplantation. As a result, HCC patients are usually left with an infaust prognosis. Thus, new therapeutic approaches are eagerly needed. 2,3 Up-regulation of growth/survival factors and their respective receptors is known to drive the formation, progression, and dissemination of HCC cells within the body. 2-4 Recently, we and others found overexpression of fibroblast growth factor (FGF) receptor (FGFR) 3 and/or FGFR4 in the majority of HCC cases and relatively rare up-regulation of FGFR1 and/or FGFR2, which was confirmed in the present study (Supporting Fig. 1). 5,6 Meanwhile, it is known that FGFR4 is involved in the

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“…26 FGFR4 is involved in myogenesis and muscle regeneration with a particular autophosphorylation rate and tyrosine kinase activity compared to other FGFRs. 27 Moreover, although FGFR5 has many unclear functions, recent studies indicated that FGFR5 may provide a binding site for one or more FGFs which regulates pancreatic function. 18 …”

Section: Structure and Physiological Function Of Fgfrsmentioning

confidence: 99%

Fibroblast growth factor receptors in breast cancer

Wang

Ding

2017

Tumour Biol.

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Fibroblast growth factor receptors are growth factor receptor tyrosine kinases, exerting their roles in embryogenesis, tissue homeostasis, and development of breast cancer. Recent genetic studies have identified some subtypes of fibroblast growth factor receptors as strong genetic loci associated with breast cancer. In this article, we review the recent epidemiological findings and experiment results of fibroblast growth factor receptors in breast cancer. First, we summarized the structure and physiological function of fibroblast growth factor receptors in humans. Then, we discussed the common genetic variations in fibroblast growth factor receptors that affect breast cancer risk. In addition, we also introduced the potential roles of each fibroblast growth factor receptors isoform in breast cancer. Finally, we explored the potential therapeutics targeting fibroblast growth factor receptors for breast cancer. Based on the biological mechanisms of fibroblast growth factor receptors leading to the pathogenesis in breast cancer, targeting fibroblast growth factor receptors may provide new opportunities for breast cancer therapeutic strategies.

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Structural Analysis of the Human Fibroblast Growth Factor Receptor 4 Kinase

Cited by 40 publications

References 54 publications

Biophysical characterization of drug‐resistant mutants of fibroblast growth factor receptor 1

Biophysical characterization of drug‐resistant mutants of fibroblast growth factor receptor 1

Fibroblast growth factor receptor 3 isoforms: Novel therapeutic targets for hepatocellular carcinoma?

Fibroblast growth factor receptors in breast cancer

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