Roles of Fibroblast Growth Factor Receptors in Carcinogenesis

Haugsten, Ellen Margrethe; Wiedlocha, Antoni G; Olsnes, Sjur; Wesche, Jørgen

doi:10.1158/1541-7786.mcr-10-0168

Cited by 271 publications

(225 citation statements)

References 189 publications

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“…At least 3 classes of mechanisms have been described that can lead to dysregulation of FGFR activity in solid tumors (1,3). First, FGFRs can be dysregulated by overexpression, for example, via gene amplification, as detected in gastric, breast, lung, and colon cancers (1,4,8).…”

Section: Discussionmentioning

confidence: 99%

“…Germ line gain-of-function mutations in FGFRs have been linked to various human diseases, most commonly FGFR2 in craniosynostosis syndromes and FGFR3 in chondrodysplasia syndromes (1,2). Many of these same mutations, and a variety of other genetic alterations that affect expression or activity of all 4 FGFRs, have been identified in multiple tumor types suggesting FGFRs as potential therapeutic targets in cancer (1)(2)(3).…”

Section: Introductionmentioning

confidence: 99%

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Ponatinib (AP24534), a Multitargeted Pan-FGFR Inhibitor with Activity in Multiple FGFR-Amplified or Mutated Cancer Models

Gozgit¹,

Wong²,

Moran³

et al. 2012

Molecular Cancer Therapeutics

287

206

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Members of the fibroblast growth factor receptor family of kinases (FGFR1-4) are dysregulated in multiple cancers. Ponatinib (AP24534) is an oral multitargeted tyrosine kinase inhibitor being explored in a pivotal phase II trial in patients with chronic myelogenous leukemia due to its potent activity against BCR-ABL. Ponatinib has also been shown to inhibit the in vitro kinase activity of all four FGFRs, prompting us to examine its potential as an FGFR inhibitor. In Ba/F3 cells engineered to express activated FGFR1-4, ponatinib potently inhibited FGFR-mediated signaling and viability with IC 50 values <40 nmol/L, with substantial selectivity over parental Ba/F3 cells. In a panel of 14 cell lines representing multiple tumor types (endometrial, bladder, gastric, breast, lung, and colon) and containing FGFRs dysregulated by a variety of mechanisms, ponatinib inhibited FGFR-mediated signaling with IC 50 values <40 nmol/L and inhibited cell growth with GI 50 (concentration needed to reduce the growth of treated cells to half that of untreated cells) values of 7 to 181 nmol/L. Daily oral dosing of ponatinib (10-30 mg/kg) to mice reduced tumor growth and inhibited signaling in all three tumor models examined. Importantly, the potency of ponatinib in these models is similar to that previously observed in BCR-ABL-driven models and plasma levels of ponatinib that exceed the IC 50 values for FGFR1-4 inhibition can be sustained in patients. These results show that ponatinib is a potent pan-FGFR inhibitor and provide strong rationale for its evaluation in patients with FGFR-driven cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ponatinib (AP24534), a Multitargeted Pan-FGFR Inhibitor with Activity in Multiple FGFR-Amplified or Mutated Cancer Models

Gozgit¹,

Wong²,

Moran³

et al. 2012

Molecular Cancer Therapeutics

287

206

View full text Add to dashboard Cite

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“…Therefore, FGFs play an important role during development and adult life. The activation of FGFR by FGF binding triggers cellular processes, such as cell proliferation, growth, differentiation, migration, and survival (E.M. Haugsten et al, 2010a;Haugsten et al, 2010b).…”

Section: Fibroblast Growth Factormentioning

confidence: 99%

“…The FGFR is a tyrosine kinase receptor, thus once the ligand binds to the receptor causes the dimerization of their intracellular domains. This changing in the intracellular structure leads to an autophosphorylation of tyrosine residues that causes the activation of several downstream transduction pathways (Haugsten et al, 2010a;Haugsten et al, 2010b). When the intracellular domain of the receptor is phosphorylated, it activates pathways that lead to the further expansion of the signal.…”

Section: Fgf/fgfr Signaling Pathwaymentioning

confidence: 99%

FGFR a promising druggable target in cancer: Molecular biology and new drugs

Porta

Borea²,

Coelho³

et al. 2017

Critical Reviews in Oncology/Hematology

167

152

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Introduction The Fibroblast Growth Factor Receptor (FGFR) family consists of Tyrosine Kinase Receptors (TKR) involved in several biological functions. Recently, alterations of FGFR have been reported to be important for progression and development of several cancers. In this setting, different studies are trying to evaluate the efficacy of different therapies targeting FGFR. Areas Covered This review summarizes the current status of treatments targeting FGFR, focusing on the trials that are evaluating the FGFR profile as inclusion criteria: Multi-Target, Pan-FGFR Inhibitors and anti-FGF (Fibroblast Growth Factor)/FGFR Monoclonal Antibodies. Expert opinion Most of the TKR share intracellular signaling pathways; therefore, cancer cells tend to overcome the inhibition of one tyrosine kinase receptor by activating another. The future of TKI (Tyrosine Kinase Inhibitor) therapy will potentially come from multi-targeted TKIs that target different TKR simultaneously. It is crucial to understand the interaction of the FGF-FGFR axis with other known driver TKRs. Based on this, it is possible to develop therapeutic strategies targeting multiple connected TKRs at once. One correct step in this direction is the reassessment of multi target inhibitors considering the FGFR status of the tumor. Another opportunity arises from assessing the use of FGFR TKI on patients harboring FGFR alterations

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Sokołowska-Wędzina

Chodaczek

Chudzian

et al. 2017

Molecular Cancer Research

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Targeted delivery of anticancer drugs using antibodies specific for tumor-associated antigens represents one of the most important approaches in current immuno-oncology research. Fibroblast growth factor receptor 1 (FGFR1) has been demonstrated to be a high-frequency targetable oncogene specific for smokingassociated lung cancers, present in over 20% of lung squamous cell carcinoma cases. This report describes the generation of a potent, fully human antibody fragment in scFv-Fc format efficiently targeting FGFR1. Antibody phage display was used to select high-affinity scFv antibody fragments against the extracellular domain of FGFR1(IIIc). Enzyme immunoassay (ELISA) and surface plasmon resonance (SPR) analysis were used for antibody screening and characterization. The best binder (named D2) was cloned to diabody and Fc fusion formats. All D2 antibodies demonstrated high affinity for FGFR1 with dissociation constants of 18 nmol/L (scFvD2), 0.82 nmol/L (scFvD2 diabody), and 0.59 nmol/L (scFvD2-Fc). scFvD2 was found to be exquisitely selective for FGFR1 versus other FGFR family members and bound FGFR1 even in the presence of its natural ligand FGF2, as shown by competitive analysis. Confocal microscopy revealed that scFvD2-Fc was specifically and rapidly internalized by a panel of cell lines overexpressing FGFR1. Finally, it was demonstrated that scFvD2-Fc mediated specific delivery of a cytotoxic payload into lung cancer cells harboring oncogenic FGFR1 gene amplifications.Implications: This study reports a highly specific internalizing antibody fragment that can serve as a therapeutic targeting agent for efficient delivery of cytotoxic drugs into FGFR1-positive lung cancer cells. Mol Cancer Res; 15(8); 1040-50. Ó2017 AACR.

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Roles of Fibroblast Growth Factor Receptors in Carcinogenesis

Cited by 271 publications

References 189 publications

Ponatinib (AP24534), a Multitargeted Pan-FGFR Inhibitor with Activity in Multiple FGFR-Amplified or Mutated Cancer Models

Ponatinib (AP24534), a Multitargeted Pan-FGFR Inhibitor with Activity in Multiple FGFR-Amplified or Mutated Cancer Models

FGFR a promising druggable target in cancer: Molecular biology and new drugs

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

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