FGFR a promising druggable target in cancer: Molecular biology and new drugs

Abstract

Introduction The Fibroblast Growth Factor Receptor (FGFR) family consists of Tyrosine Kinase Receptors (TKR) involved in several biological functions. Recently, alterations of FGFR have been reported to be important for progression and development of several cancers. In this setting, different studies are trying to evaluate the efficacy of different therapies targeting FGFR. Areas Covered This review summarizes the current status of treatments targeting FGFR, focusing on the trials that are evaluating the FGFR profile as inclusion criteria: Multi-Target, Pan-FGFR Inhibitors and anti-FGF (Fibroblast Growth Factor)/FGFR Monoclonal Antibodies. Expert opinion Most of the TKR share intracellular signaling pathways; therefore, cancer cells tend to overcome the inhibition of one tyrosine kinase receptor by activating another. The future of TKI (Tyrosine Kinase Inhibitor) therapy will potentially come from multi-targeted TKIs that target different TKR simultaneously. It is crucial to understand the interaction of the FGF-FGFR axis with other known driver TKRs. Based on this, it is possible to develop therapeutic strategies targeting multiple connected TKRs at once. One correct step in this direction is the reassessment of multi target inhibitors considering the FGFR status of the tumor. Another opportunity arises from assessing the use of FGFR TKI on patients harboring FGFR alterations

Inhibitive Effects of FGF2/FGFR1 Pathway on Astrocyte-Mediated Inflammation in vivo and in vitro After Infrasound Exposure

“…Previous studies have showed that FGF2 could exert a positive feedback effect by upregulating FGFR1, its own receptor (Woodbury and Ikezu, 2014; Porta et al, 2017; Yuan et al, 2017). Therefore, we examined whether exogenous FGF2 also changed FGFR1 expression after infrasound exposure.…”

Prognostic importance of FGF2 and FGFR1 expression for patients affected by ameloblastoma

“…Alternative splicing generates two different isoforms (b/c) of the IgIII domain in each of the receptors, but not in FGFR4. Recently, FGFR5 was described, but with no intracellular tyrosine kinase domain …”

“…As FGF‐FGFR family of proteins are important prognostic factors for different neoplasms, a large number of potential inhibitors of these molecules are currently being investigated to be used as targeted therapies. These drugs are usually classified as non‐selective FGFR TKR inhibitors (Brigatinib, Lenvatinib, Regorafenib, and others), selective FGF TKR inhibitors (AZD4547, BGJ398, LY2874455), and others), antibodies against FGF and FGFR (GP369, GAL‐FR21, GAL‐FR22, and others) . Therefore, the development of these inhibitors may potentially be useful for the management of ameloblastoma, but more studies are necessary to confirm the clinical importance of FGF‐FGFR components for ameloblastoma behavior.…”

Adipose stem cell crosstalk with chemo-residual breast cancer cells: implications for tumor recurrence

“…The classes of compounds presently in use or in clinical trials are selective and non-selective tyrosine kinase inhibitors, such as BGJ398, as well as monoclonal antibodies and FGF-ligand traps described previously. To qualify for treatment or to participate in clinical trials with these agents, patients must meet eligibility criteria, including possession of known FGFR mutations, amplifications, or translocations [24]. In the present study, we demonstrate that FGF2 signaling from stromal cells plays a key role in supporting the tumor microenvironment suggesting that many patients that do not presently meet eligibility criteria for FGFR inhibitor treatment may in fact benefit from these drugs because of their ability to inhibit ASC paracrine signaling.…”

“…FGFR tyrosine kinase inhibitors are used as a treatment modality in patients to slow the growth of tumors across a wide array of cancer types including breast, prostate, lymphoma, multiple myeloma, and urothelial carcinoma [24]. The classes of compounds presently in use or in clinical trials are selective and non-selective tyrosine kinase inhibitors, such as BGJ398, as well as monoclonal antibodies and FGF-ligand traps described previously.…”