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.
Highlights
The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) is a receptor tyrosine kinase (RTK) signaling pathway that fundamentally regulates embryogenesis, angiogenesis, tissue homeostasis, and wound repair [1, 2]
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; a deeper understanding of biomarker strategies is undoubtedly warranted
The FGF/FGFR pathway demonstrates yet another mechanism that is critically involved in oncogenesis, thereby providing an actionable target for inhibition and exploitation of cell signaling
Summary
The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) is a receptor tyrosine kinase (RTK) signaling pathway that fundamentally regulates embryogenesis, angiogenesis, tissue homeostasis, and wound repair [1, 2]. Receptor overexpression can be a result of gene amplification or changes in post-transcriptional processing; point mutations may result in constitutive receptor activation or decreased sensitivity to ligand binding; translocations can produce fusion proteins with constitutive activity; and isoform switching and alternative splicing can reduce specificity to FGFs [22]. These major oncogenic aberrations represent features that make FGFR an ideal therapeutic target for treating a broad scope of malignancies. Asymptomatic RPED occurred in 1 pt NCT01795768 [90]
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