In hepatocytes, for instance, FGF19-FGFR4 induces activation of the JNK signaling pathway, which results in reduced bile acid synthesis via repression of the critical enzyme CYP7A1 . factor receptor (FGFR) pathway. FGFRs are involved in many aspects of cancer formation, such as cell proliferation, differentiation, and growth. Importantly, FGFRs are frequently mutated in BC, and their overexpression and/or hyperactivation correlates with CDK4/6 inhibitor resistance and shortened PFS in BC. Intriguingly, the inhibition of aberrant FGFR activity is capable of reversing the resistance to CDK4/6 inhibitors. This review summarizes the molecular background of FGFR signaling and discusses the role of aberrant FGFR signaling during cancer development in general and during the development of CDK4/6 inhibitor resistance in BC in particular, together with other possible mechanisms for resistance to CDK4/6 inhibitors. Subsequently, future NCT-502 directions on novel therapeutic strategies targeting FGFR signaling to overcome such resistance during BC treatment will be further debated. alterations during the development of resistance to CDK4/6 inhibitors and how targeting the FGFR pathway could be utilized therapeutically to overcome CDK4/6 inhibitor therapy resistance in BC will be further debated. 2. Biology of FGFR Signaling Fibroblast growth factor receptors constitute a family of four single-pass transmembrane receptors (FGFR1C4) with an intracellular tyrosine kinase domain. They become activated upon the extracellular binding of their cognate ligands from the fibroblast growth factor (FGF) family. To this end, their extracellular parts contain three immunoglobulin (Ig)-like domains (IgI-IgIII), as well as an acidic region between IgI and IgII. While IgI and the acidic region seem to play an NCT-502 inhibitory role, the IgII and IgIII domains cooperate in ligand binding . Interestingly, alternative splicing of the NCT-502 third Ig-like domain (IgIII) in FGFR1C3 yields two additional isoforms, namely IIIb and IIIc, which are mainly expressed in epithelial and mesenchymal tissues, respectively [7,8]. Similarly, the functional relevance of distinct family members is tissue-specific to some NCT-502 extent, with FGFR1 and FGFR3 being more important in mesenchymal cells and FGFR2 becoming more relevant in epithelial cells . The diversity of receptor constructions yields receptors with different binding affinities for the plethora of FGF ligands [10,11]. In addition, a fifth FGFR-like protein has been identified (FGFR5/FGFRL1), which can also bind FGF ligands but lacks the tyrosine kinase website essential for intracellular signaling . However, FGFR5 may be involved in FGFR signaling by functioning like a coreceptor for FGFR1 . While the nature of the ligand, as well as tissue-specific manifestation and splicing of the four FGFR receptor tyrosine kinases determine the precise cellular end result of FGFR signaling, the activation of intracellular signaling cascades regularly impinge within the pathways involved in proliferation, cellular survival, and differentiation. Therefore, FGF-FGFR signaling mediates multiple physiological processes such as organ development, tissue homeostasis, rate of metabolism, wound restoration, and angiogenesis. Since most of the specificity of FGF-FGFR signaling can be attributed to the nature of the ligand, it is not surprising the FGF family comprises a large and functionally varied group of proteins. In humans, this family consists of 22 users and may become divided into three major organizations. First, the group of 15 canonical (or paracrine) FGF ligands functions in an autocrine or paracrine fashion by binding to FGFRs in complex with extracellular heparan sulfate proteoglycans (HSPGs). HSPGs are important for this signaling, since they protect FGFs from degradation and stabilize the connection between FGFs and FGFRs. Canonical FGF ligands can be further divided into five subfamilies, i.e., the FGF1/2, FGF4/5/6, FGF3/7/10/22, FGF8/17/18, and FGF9/16/20 subfamilies. Second, the group of endocrine FGF ligands (FGF19/21/23) Rabbit Polyclonal to HBP1 also binds to FGFRs but utilizes Klotho or -Klotho as coreceptors and does not bind to HSPGs. Consequently, they are capable of diffusing into the bloodstream and act as hormones. Most notably, they regulate bile acid synthesis,.