title: Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application.
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.
authors.affiliation: Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA.|Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Young Kwang
authors.initials: YK
authors.lastname: Chae
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Keerthi
authors.initials: K
authors.lastname: Ranganath
authors.affiliation: Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hammerman
authors.affiliation: Division of Hematology Oncology, University of Alabama Birmingham, Birmingham, AL, USA.
authors.forename: Christos
authors.initials: C
authors.lastname: Vaklavas
authors.affiliation: Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA.|Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Nisha
authors.initials: N
authors.lastname: Mohindra
authors.affiliation: Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA.|Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Aparna
authors.initials: A
authors.lastname: Kalyan
authors.affiliation: Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA.|Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Matsangou
authors.affiliation: Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Costa
authors.affiliation: Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA.|Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Benedito
authors.initials: B
authors.lastname: Carneiro
authors.affiliation: Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA.|Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Villaflor
authors.affiliation: Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA.|Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Cristofanilli
authors.affiliation: Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA.|Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
mesh_terms: D006801:Humans; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D017468:Receptors, Fibroblast Growth Factor
keywords: factor; fibroblast; growth; inhibition; receptor