Loss-of-Function Fibroblast Growth Factor Receptor-2 Mutations in Melanoma

Gartside, Michael G.; Chen, Huaibin; Ibrahimi, Omar A.; Byron, Sara A.; Curtis, Amy V.; Wellens, Candice L.; Bengston, Ana; Yudt, Laura M.; Eliseenkova, Anna V.; Ma, Jinghong; Curtin, John A.; Hyder, Pilar; Harper, Ursula L.; Riedesel, Erica L.; Mann, Graham J.; Trent, Jeffrey M.; Bastian, Boris C.; Meltzer, Paul S.; Mohammadi, Moosa; Pollock, Pamela M.

doi:10.1158/1541-7786.mcr-08-0021

Cited by 112 publications

(91 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…2C , extracellular domain; ref. 31 ) in cis with the V472M "gatekeeper" mutation that induces resistance to FGFR inhibition ( 6 ). As expected, ectopic expression of the V472M gatekeeper mutation alone resulted in resistance to FGFR inhibition in H1581 cells ( Fig.…”

Section: Control Virussupporting

confidence: 64%

See 1 more Smart Citation

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of Transformation by Amplified FGFR1 in Lung Cancer

et al. 2014

View full text Add to dashboard Cite

The 8p12 locus (containing the FGFR1 tyrosine kinase gene) is frequently amplifi ed in squamous cell lung cancer. However, it is currently unknown which of the 8p12-amplifi ed tumors are also sensitive to fi broblast growth factor receptor (FGFR) inhibition. We found that, in contrast with other recurrent amplifi cations, the 8p12 region included multiple centers of amplifi cation, suggesting marked genomic heterogeneity. FGFR1 -amplifi ed tumor cells were dependent on FGFR ligands in vitro and in vivo . Furthermore, ectopic expression of FGFR1 was oncogenic, which was enhanced by expression of MYC. We found that MYC was coexpressed in 40% of FGFR1 -amplifi ed tumors. Tumor cells coexpressing MYC were more sensitive to FGFR inhibition, suggesting that patients with FGFR1-amplifi ed and MYC-overexpressing tumors may benefi t from FGFR inhibitor therapy. Thus, both cell-autonomous and non-cell-autonomous mechanisms of transformation modulate FGFR dependency in FGFR1 -amplifi ed lung cancer, which may have implications for patient selection for treatment with FGFR inhibitors. SIGNIFICANCE:Amplifi cation of FGFR1 is one of the most frequent candidate targets in lung cancer. Here, we show that multiple factors affect the tumorigenic potential of FGFR1 , thus providing clinical hypotheses for refi nement of patient selection. Cancer Discov; 4(2);

show abstract

Section: Control Virussupporting

confidence: 64%

“…2C and D ), which is analogous to the R251Q mutation of FGFR2. This mutation strongly interferes with ligand binding to FGFR2 ( 31 ). We further predicted fi ve other extracellular mutation sites in the Inter-IgG2-IgG3 domain (ref.…”

Section: Control Virusmentioning

confidence: 93%

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of Transformation by Amplified FGFR1 in Lung Cancer

et al. 2014

View full text Add to dashboard Cite

show abstract

“…FGFR1 overexpression (14) and activating FGFR1 gene mutation (49) have been also reported in melanoma. Finally, approximately 10% of melanoma tumors and melanoma cell lines harbor inactivating, loss-of-function mutations in the FGFR2 gene (50). The ability to interact with different FGFs without interacting with FGFRs makes PTX3 a multitarget "FGF ligand trap" for those lesions characterized by an aberrant production of one or multiple FGF family members.…”

Section: Discussionmentioning

confidence: 99%

Long Pentraxin-3 Inhibits Epithelial–Mesenchymal Transition in Melanoma Cells

Ronca

Salle

Giacomini

et al. 2013

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

During melanoma progression, malignant melanocytes are reprogrammed into mesenchymal-like cells through to an epithelial-mesenchymal transition (EMT) process associated with the acquisition of an invasive, prometastatic phenotype. The fibroblast growth factor-2 (FGF2)/FGF receptor (FGFR) system plays a pivotal role in melanoma, leading to autocrine/paracrine induction of tumor cell proliferation and angiogenesis. Long pentraxin-3 (PTX3) interacts with FGF2, and other FGF family members, inhibiting FGF-dependent neovascularization and tumor growth. Here, PTX3 protein and the PTX3-derived acetylated pentapeptide Ac-ARPCA-NH 2 inhibit FGF2-driven proliferation and downstream FGFR signaling in murine melanoma B16-F10 cells. Moreover, human PTX3-overexpressing hPTX_B16-F10 cells are characterized by the reversed transition from a mesenchymal to an epithelial-like appearance, inhibition of cell proliferation, loss of clonogenic potential, reduced motility and invasive capacity, downregulation of various mesenchymal markers, and upregulation of the epithelial marker E-cadherin. Accordingly, PTX3 affects cell proliferation and EMT transition in human A375 and A2058 melanoma cells. Also, hPTX_B16-F10 cells showed a reduced tumorigenic and metastatic activity in syngeneic C57BL/6 mice. In conclusion, PTX3 inhibits FGF/FGFR-driven EMT in melanoma cells, hampering their tumorigenic and metastatic potential. These data represent the first experimental evidence about a nonredundant role of the FGF/FGFR system in the modulation of the EMT process in melanoma and indicate that PTX3 or its derivatives may represent the basis for the design of novel therapeutic approaches in FGF/FGFRdependent tumors, including melanoma. Mol Cancer Ther; 12(12); 2760-71. Ó2013 AACR.

show abstract

“…To control for nonspecific binding, the FGFR2c R251Q mutant was coupled to the control flow channel of the chip. The R251Q mutation maps to the linker region between D2 and D3 of FGFR2c, and we have previously shown that this mutation results in a major loss of ligand binding because it eliminates key hydrogen bonds between FGFR and FGF (64). To examine binding of mutated FGFR2b ligand-binding regions to FGF1, full-length FGF1 was immobilized on a chip, and FGFR2b…”

Section: Methodsmentioning

confidence: 99%

Plasticity in Interactions of Fibroblast Growth Factor 1 (FGF1) N Terminus with FGF Receptors Underlies Promiscuity of FGF1

Beenken¹,

Eliseenkova²,

Ibrahimi³

et al. 2012

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Tissue-specific alternative splicing in the second half of Iglike domain 3 (D3) of fibroblast growth factor receptors 1-3 (FGFR1 to -3) generates epithelial FGFR1b-FGFR3b and mesenchymal FGFR1c-FGFR3c splice isoforms. This splicing event establishes a selectivity filter to restrict the ligand binding specificity of FGFRb and FGFRc isoforms to mesenchymally and epithelially derived fibroblast growth factors (FGFs), respectively. FGF1 is termed the "universal FGFR ligand" because it overrides this specificity barrier. To elucidate the molecular basis for FGF1 cross-reactivity with the "b" and "c" splice isoforms of FGFRs, we determined the first crystal structure of FGF1 in complex with an FGFRb isoform, FGFR2b, at 2.1 Å resolution. Comparison of the FGF1-FGFR2b structure with the three previously published FGF1-FGFRc structures reveals that plasticity in the interactions of the N-terminal region of FGF1 with FGFR D3 is the main determinant of FGF1 cross-reactivity with both isoforms of FGFRs. In support of our structural data, we demonstrate that substitution of three N-terminal residues (Gly-19, His-25, and Phe-26) of FGF2 (a ligand that does not bind FGFR2b) for the corresponding residues of FGF1 (Phe-16, Asn-22, and Tyr-23) enables the FGF2 triple mutant to bind and activate FGFR2b. These findings taken together with our previous structural data on receptor binding specificity of FGF2, FGF8, and FGF10 conclusively show that sequence divergence at the N termini of FGFs is the primary regulator of the receptor binding specificity and promiscuity of FGFs.Fibroblast growth factor (FGF) signaling plays pleiotropic roles in mammalian development and metabolism (1-3). The mammalian FGF family comprises 18 members (FGF1-FGF10 and FGF16 -FGF23), which are divided into six subfamilies based on sequence homology and phylogeny. The FGF1 subfamily comprises FGF1 and FGF2; the FGF7 subfamily comprises FGF3, FGF7, FGF10, and FGF22; the FGF4 subfamily comprises FGF4, FGF5, and FGF6; the FGF8 subfamily comprises FGF8, FGF17, and FGF18; the FGF9 subfamily comprises FGF9, FGF16, and FGF20; and the FGF19 subfamily consists of FGF19, FGF21, and FGF23 (4, 5). In some nomenclatures, FGF homologous factors (FHF1-FHF4) 6 are considered to form an additional FGF subfamily, namely the FGF11 subfamily, because these proteins share strong sequence homology to other FGFs. Biochemical and structural analyses of FHFs, however, have shown that these proteins are functionally distinct from FGFs (6 -8). The FGF1, FGF4, FGF7, FGF8, and FGF9 subfamilies act in a paracrine fashion to direct tissue patterning and organogenesis during embryogenesis. In contrast, the FGF19 subfamily members have very low affinity for heparan sulfate (HS) and hence act in an endocrine fashion (9) to regulate important metabolic activities, including bile acid and lipid metabolism (10 -13), glucose homeostasis (14 -17), and phosphate and vitamin D homeostasis (18 -20).The paracrine FGFs carry out their diverse functions by binding and activating the FGF receptor (FGFR)...

show abstract

Loss-of-Function Fibroblast Growth Factor Receptor-2 Mutations in Melanoma

Cited by 112 publications

References 39 publications

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of Transformation by Amplified FGFR1 in Lung Cancer

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of Transformation by Amplified FGFR1 in Lung Cancer

Long Pentraxin-3 Inhibits Epithelial–Mesenchymal Transition in Melanoma Cells

Plasticity in Interactions of Fibroblast Growth Factor 1 (FGF1) N Terminus with FGF Receptors Underlies Promiscuity of FGF1

Contact Info

Product

Resources

About