Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application - PubMed (original) (raw)

Review

. 2017 Feb 28;8(9):16052-16074.

doi: 10.18632/oncotarget.14109.

Young Kwang Chae 1 2 3, Peter S Hammerman 4, Christos Vaklavas 5, Nisha Mohindra 1 2 3, Aparna Kalyan 1 2 3, Maria Matsangou 1 2 3, Ricardo Costa 1, Benedito Carneiro 1 2 3, Victoria M Villaflor 1 2 3, Massimo Cristofanilli 1 2 3, Francis J Giles 1 2 3

Affiliations

Review

Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application

Young Kwang Chae et al. Oncotarget. 2017.

Abstract

The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) is a tyrosine kinase signaling pathway that has a fundamental role in many biologic processes including embryonic development, tissue regeneration, and angiogenesis. Increasing evidence indicates that this pathway plays a critical role in oncogenesis via gene amplification, activating mutations, or translocation in tumors of various histologies. With multiplex sequencing technology, the detection of FGFR aberrations has become more common and is tied to cancer cell proliferation, resistance to anticancer therapies, and neoangiogenesis. Inhibition of FGFR signaling appears promising in preclinical studies, suggesting a pathway of clinical interest in the development of targeted therapy. Phase I trials have demonstrated a manageable toxicity profile. Currently, there are multiple FGFR inhibitors under study with many non-selective (multi-kinase) inhibitors demonstrating limited clinical responses. As we progress from the first generation of non-selective drugs to the second generation of selective FGFR inhibitors, it is clear that FGFR aberrations do not behave uniformly across cancer types; thus, a deeper understanding of biomarker strategies is undoubtedly warranted. This review aims to consolidate data from recent clinical trials with a focus on selective FGFR inhibitors. As Phase II clinical trials emerge, concentration on patient selection as it pertains to predicting response to therapy, feasible methods for overcoming toxicity, and the likelihood of combination therapies should be utilized. We will also discuss qualities that may be desirable in future generations of FGFR inhibitors, with the hope that overcoming these current barriers will expedite the availability of this novel class of medications.

Keywords: factor; fibroblast; growth; inhibition; receptor.

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Conflict of interest statement

Conflicts of interest

No relevant conflicts of interests to report.

Figures

Figure 1

Figure 1. Molecular aberrations leading to FGFR pathway activation

The FGFRs dimerize upon ligand binding and trigger a downstream cascade of signaling pathways. The FGFR receptors (1-4) can become activated by mutation, translocation, or gene amplification. An increase in circulating FGF ligands can also cause activation. Downstream signaling can trigger the mitogen activated protein kinase (MAPK) pathway, the phosphoinositide-3-kinase (PI3K/Akt) pathway, the phosphorylation of the signal transducer and activator of transcription (STAT), and the PLCγ activation of the DAG-PKC and IP3-Ca2+ cascade resulting in DNA transcription. Negative feedback loops can attenuate the signaling cascade at varying levels. As seen above, the “similar expression to FGF” (SEF) family members can interact with the cytoplasmic domain of FGFRs and inhibit downstream signaling. It is hypothesized that FGFRL1 (atypical receptor/FGFR5) may serve as a ligand trap, may dimerize with other transmembrane FGFRs and inhibit autophosphorylation, or may increase turnover rates of other FGFRs [16]. No evidence exists for these mechanisms.

Figure 2

Figure 2. Selected overview of phase II clinical trials evaluating FGFR Inhibitors as monotherapy or in combination with existing therapies

Bladder, Lung, and Gastric cancers all are areas of interest in advanced clinical trials testing FGFR pathway inhibition. There exist a wide scope of histologies where FGFR inhibition may be of clinical benefit, many phase II trials are currently in the recruiting stages or are actively ongoing.

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