Binding of FGFs to FGFRs leads

Binding of FGFs to FGFRs leads to receptor dimerization, resulting in the transphosphorylation of a tyrosine in the activation loop of the kinase domain. Subsequently, the activated FGFRs phosphorylate their intracellular receptor substrates, particularly FGFR substrate 2 (FRS2) and phospholipase Cγ (PLCγ). On one hand, activated FRS2 promotes downstream signaling through the RAS–mitogen-activated protein kinase (MAPK) or the phosphoinositide 3-kinase (PI3K)–AKT pathways that regulate cell proliferation, differentiation, and survival. On the other hand, the activation of PLCγ leads to the release of calcium ions from the intracellular compartment and to the activation of calcium-dependent signaling, events that mediate cell motility. Moreover, there are other choline fenofibrate mg proteins activated by FGFRs, such as Signal Transducers and Activators of Transcription (STAT) factors, Src, and RAF, through the stimulation of protein kinase C (Fig. 1) [17].
Genomic aberrations of the FGF/FGFR signaling pathway in breast cancer The FGF/FGFR signaling pathway is frequently deregulated in human cancers. Overall, FGFR alterations have been found in 7.1% of cancers, with the majority being gene amplifications (66% of the aberrations), followed by mutations (26%) and rearrangements (8%) [18]. Tumor types most commonly affected are urothelial (32% FGFR-aberrant), breast (18%), endometrial (∼13%), squamous lung cancers (∼13%), and ovarian cancer (∼9%). Moreover, ligand-dependent mechanisms are also responsible of the aberrant activation of FGFR signaling through the paracrine and/or autocrine production of FGFs proteins by stromal and/or tumor cells. In breast cancer, FGFR1 amplification represents the most frequent genomic aberration, whereas amplification of FGFR2–4 genes and FGFR activating mutations are uncommon. These alterations are discussed further in the following sections (Table 1).
Role of the FGF/FGFR signaling pathway in the treatment of breast cancer Preclinical data have consistently shown that FGFR1-and FGFR2-amplified breast cancer cell lines and xenografts are more sensitive than nonamplified models to growth inhibition by FGFR inhibitors [29], [30]. Moreover, alterations in the FGF/FGFR signaling pathway may also have important clinical implications in breast cancer patients. Despite the fact that the role of FGFR2 amplification in the management of breast cancer remains unclear, several studies have confirmed the clinical and biological importance of FGFR1 amplification. Initially, Elbauomy Elsheikh et al. reported that FGFR1 gene amplification was significantly correlated with shorter overall survival, mainly in HR-positive breast cancer [19]. Subsequently, Turner et al. confirmed an association between FGFR1 gene amplification and resistance to endocrine therapy, also demonstrating a worse distant metastasis-free survival in FGFR1-overexpressing tumors and a higher frequency of FGFR1 amplification in the luminal B subtype [31]. In their work, FGFR1-amplified cell lines showed resistance to 4-hydroxytamoxifen, an active metabolite of tamoxifen, which was abrogated by small interfering RNA silencing of FGFR1. In line with these findings, FGFR1 gene amplification has been associated with shorter time to progression on first-line endocrine therapy in patients with HR-positive metastatic breast cancer [20], [32]. More recently, FGFR1 gene amplification has also been suggested as a predictive marker for lack of efficacy of cyclin-dependent kinase (CDK) 4 and CDK6 inhibitors [33]. Experiments in vitro have shown that FGFR1-amplified cell lines and xenografts are relatively resistant to estrogen deprivation, fulvestrant, and palbociclib compared to FGFR1-nonamplified models. This resistance was reversed with FGFR tyrosine kinase inhibitors (TKIs). Finally, Hanker et al. have demonstrated that trastuzumab-resistant xenografts exhibit an FGF3, FGF4, and FGF19 copy number gains, along with an increase in FGFR phosphorylation, and stimulation of BT474 HER2-positive cell lines with FGF4 promotes resistance to lapatinib and trastuzumab in vitro that can be overcomed with FGFR TKIs [34]. Furthermore, high expression of FGFR1 has been correlated with a statistically shorter progression-free survival (PFS) in patients with HER2-positive early breast cancer treated with adjuvant trastuzumab, and FGFR1 and/or FGF3 gene amplification has been associated with a lower pathological complete response in patients with HER2-positive early breast cancer treated with neoadjuvant anti-HER2 therapy.