Fibroblast Growth Factor Receptors as Therapeutic Targets in Human Melanoma: Synergism with BRAF Inhibition

Metzner, Thomas; Bedeir, Alexandra; Held, Gerlinde; Peter-Vörösmarty, Barbara; Ghassemi, Sara; Heinzle, Christine; Spiegl-Kreinecker, Sabine; Marian, Brigitte; Holzmann, Klaus; Grasl‐Kraupp, Bettina; Pirker, Christine; Micksche, M.; Berger, Walter; Heffeter, Petra; Grusch, Michael

doi:10.1038/jid.2011.177

Cited by 69 publications

(81 citation statements)

References 42 publications

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“…Moreover, treatment with recombinant PTX3 protein similarly affected cell proliferation and EMT in BRAFmutated human A375 and A2058 melanoma cells. In keeping with these observations, blockade of FGF signals by dominant-negative receptors or tyrosine kinase inhibitors reduces melanoma growth and synergistically enhances the antimelanoma effect of BRAF inhibition (16).…”

Section: Discussionmentioning

confidence: 75%

“…A preliminary analysis has revealed that, besides FGF2, PTX3 efficiently binds FGF8b, FGF17, and with a lower affinity FGF6 and FGF10 (22). Deregulation of the FGF/ FGFR system in melanoma may occur by overexpression of FGF2 and to a lesser extent of FGF5 and FGF18 (16). FGFR1 overexpression (14) and activating FGFR1 gene mutation (49) have been also reported in melanoma.…”

Section: Discussionmentioning

confidence: 99%

“…Also, normal melanocytes transduced with FGF2 exhibit a transformed phenotype resembling early-stage melanoma (15). Thus, the FGF2/FGFR system has been proposed as a target for melanoma therapy (9,14,16,17).…”

Section: Introductionmentioning

confidence: 99%

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

Ronca

Salle

Giacomini

et al. 2013

Molecular Cancer Therapeutics

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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.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

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

Ronca

Salle

Giacomini

et al. 2013

Molecular Cancer Therapeutics

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“…Antitumor effect of FGFR inhibitors (SU5402 and PD166866) in combination with BRAF inhibitors was shown in vitro and in vivo in a set of BRAF mutant melanoma cells [51]. The small molecule multitarget kinase inhibitor BIBF-1120 acting on FGF, VEGF and PDGF receptors inhibited the proliferation of a large panel of tumor cells including kidney, pharyngeal, ovary, lung, colon, pancreatic cancer and glioma cells in vitro and antitumor effect in vivo [52][53][54].…”

Section: Introductionmentioning

confidence: 99%

Sensitivity of Melanoma Cells to EGFR and FGFR Activation but Not Inhibition is Influenced by Oncogenic BRAF and NRAS Mutations

Garay

Molnár

Juhász

et al. 2015

Pathol. Oncol. Res.

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BRAF and NRAS are the two most frequent oncogenic driver mutations in melanoma and are pivotal components of both the EGF and FGF signaling network. Accordingly, we investigated the effect of BRAF and NRAS oncogenic mutation on the response to the stimulation and inhibition of epidermal and fibroblast growth factor receptors in melanoma cells. In the three BRAF mutant, two NRAS mutant and two double wild-type cell lines growth factor receptor expression had been verified by qRT-PCR. Cell proliferation and migration were determined by the analysis of 3-days-long time-lapse videomicroscopic recordings. Of note, a more profound response was found in motility as compared to proliferation and double wild-type cells displayed a higher sensitivity to EGF and FGF2 treatment when compared to mutant cells. Both baseline and induced activation of the growth factor signaling was assessed by immunoblot analysis of the phosphorylation of the downstream effectors Erk1/2. Low baseline and higher inducibility of the signaling pathway was characteristic in double wild-type cells. In contrast, oncogenic BRAF or NRAS mutation did not influence the response to EGF or FGF receptor inhibitors in vitro. Our findings demonstrate that the oncogenic mutations in melanoma have a profound impact on the motogenic effect of the activation of growth factor receptor signaling. Since emerging molecularly targeted therapies aim at the growth factor receptor signaling, the appropriate mutational analysis of individual melanoma cases is essential in both preclinical studies and in the clinical trials and practice.

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“…122 FGF2 is overexpressed on melanoma cells, but not on normal melanocytes, 123 and has been linked to tumor progression in multiple malignancies, including melanoma.…”

Section: Perspectivementioning

confidence: 99%

Developments in targeted therapy in melanoma

Amann

Ramelyte

Thurneysen

et al. 2017

European Journal of Surgical Oncology (EJSO)

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Melanomas are disease entities driven in part by the mitogen activated protein kinase (MAPK) pathway. The TCGA network recently defined four genetic subtypes based on the most prevalent significantly mutated genes, including mutant BRAF, mutant RAS (N/H/K), mutant NF1, and Triple wild-type melanoma (harboring none of the aforementioned mutations, but instead includes KIT, GNA and GNAQ mutations). The successful development of kinase inhibitors marked a milestone in the treatment of metastatic melanoma. Combination treatment with a BRAF-and MEK-inhibitor is the current standard of care for inoperable stage IIIC/IV BRAF-mutated melanoma. Recent data demonstrate excellent longterm outcome, especially in patients with normal baseline LDH levels, and confirm that there is a subset of BRAF inhibitor-naive patients who experience durable responses without progression on combination treatment. In the future, adding a third compound based on individual genetic alterations might further improve the outcome of targeted therapy. AbstractMelanomas are disease entities driven in part by the mitogen activated protein kinase (MAPK) pathway. The TCGA network recently defined four genetic subtypes based on the most prevalent significantly mutated genes, including mutant BRAF, mutant RAS (N/H/K), mutant NF1, and Triple wild-type melanoma (harboring none of the aforementioned mutations, but instead includes KIT, GNA and GNAQ mutations).The successful development of kinase inhibitors marked a milestone in the treatment of metastatic melanoma. Combination treatment with a BRAF-and MEK-inhibitor is the current standard of care for inoperable stage IIIC/IV BRAF-mutated melanoma. Recent data demonstrate excellent long-term outcome, especially in patients with normal baseline LDH levels, and confirm that there is a subset of BRAF inhibitor-naive patients who experience durable responses without progression on combination treatment. In the future, adding a third compound based on individual genetic alterations might further improve the outcome of targeted therapy.

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Fibroblast Growth Factor Receptors as Therapeutic Targets in Human Melanoma: Synergism with BRAF Inhibition

Cited by 69 publications

References 42 publications

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

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

Sensitivity of Melanoma Cells to EGFR and FGFR Activation but Not Inhibition is Influenced by Oncogenic BRAF and NRAS Mutations

Developments in targeted therapy in melanoma

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