Targeting Cellular Trafficking of Fibroblast Growth Factor Receptors as a Strategy for Selective Cancer Treatment

Abstract

Fibroblast growth factor receptors (FGFRs) in response to fibroblast growth factors (FGFs) transmit signals across the cell membrane, regulating important cellular processes, like differentiation, division, motility, and death. The aberrant activity of FGFRs is often observed in various diseases, especially in cancer. The uncontrolled FGFRs’ function may result from their overproduction, activating mutations, or generation of FGFRs’ fusion proteins. Besides their typical subcellular localization on the cell surface, FGFRs are often found inside the cells, in the nucleus and mitochondria. The intracellular pool of FGFRs utilizes different mechanisms to facilitate cancer cell survival and expansion. In this review, we summarize the current stage of knowledge about the role of FGFRs in oncogenic processes. We focused on the mechanisms of FGFRs’ cellular trafficking—internalization, nuclear translocation, and mitochondrial targeting, as well as their role in carcinogenesis. The subcellular sorting of FGFRs constitutes an attractive target for anti-cancer therapies. The blocking of FGFRs’ nuclear and mitochondrial translocation can lead to the inhibition of cancer invasion. Moreover, the endocytosis of FGFRs can serve as a tool for the efficient and highly selective delivery of drugs into cancer cells overproducing these receptors. Here, we provide up to date examples how the cellular sorting of FGFRs can be hijacked for selective cancer treatment.

FGFR1 clustering with engineered tetravalent antibody improves the efficiency and modifies the mechanism of receptor internalization

“…The mechanisms involved in FGFR1 internalization are only partially understood [29]. It was demonstrated that FGFR1 is subjected to constitutive, low‐rate internalization, however, FGFR1 dimerization caused by ligand binding largely accelerates uptake of the receptor [30–33].…”

“…It was demonstrated that FGFR1 is subjected to constitutive, low‐rate internalization, however, FGFR1 dimerization caused by ligand binding largely accelerates uptake of the receptor [30–33]. The efficiency and mechanism of FGFR1 internalization depend on the type of an applied ligand [29,34–39]. The uptake of FGF/FGFR1 complexes mainly occurs via clathrin‐mediated endocytosis (CME) leading to lysosomal degradation of FGFR1 [29,30,36,37,39].…”

“…The efficiency and mechanism of FGFR1 internalization depend on the type of an applied ligand [29,34–39]. The uptake of FGF/FGFR1 complexes mainly occurs via clathrin‐mediated endocytosis (CME) leading to lysosomal degradation of FGFR1 [29,30,36,37,39]. We have recently uncoupled FGFR1 dimerization from the receptor activation and have demonstrated that dimerization of FGFR1, but not receptor autophosphorylation, triggers CME of FGFR1 [5,6].…”

Differential regulation of fibroblast growth factor receptor 1 trafficking and function by extracellular galectins

“…The FGFRs-FGFs signaling is important for angiogenesis, regulation of metabolism and tissue repair [1][2][3]. The dysregulation of FGFRs leads to developmental disorders and cancer [4][5][6][7]. FGFR1 is overexpressed in lung cancers, breast cancers, osteosarcomas and in solid tumors like head and neck cancers, and it is associated with poor patient prognosis [8][9][10][11][12][13][14][15][16].…”

Promises of Fibroblast Growth Factor Receptor–Directed Therapy in Tailored Cancer Treatment

“…Due to their importance in cellular homeostasis, the expression and activity of RTKs is finely tuned, and any aberrancy in their signalling leads to disease development. Chromosomal rearrangements, gene amplifications, gain of function, alternative splicing, and autocrine activation are among the most frequent causes of oncogenic RTK signalling [ 2 , 3 ]. Among the RTKs, the fibroblast growth factor–fibroblast growth factor receptor (FGF–FGFR) axis has attracted considerable attention as a druggable target, and several therapeutic strategies have been developed for its selective targeting in cancer [ 4 ].…”