FGF/FGFR-Dependent Molecular Mechanisms Underlying Anti-Cancer Drug Resistance

Abstract

Increased expression of both FGF proteins and their receptors observed in many cancers is often associated with the development of chemoresistance, limiting the effectiveness of currently used anti-cancer therapies. Malfunctioning of the FGF/FGFR axis in cancer cells generates a number of molecular mechanisms that may affect the sensitivity of tumors to the applied drugs. Of key importance is the deregulation of cell signaling, which can lead to increased cell proliferation, survival, and motility, and ultimately to malignancy. Signaling pathways activated by FGFRs inhibit apoptosis, reducing the cytotoxic effect of some anti-cancer drugs. FGFRs-dependent signaling may also initiate angiogenesis and EMT, which facilitates metastasis and also correlates with drug resistance. Therefore, treatment strategies based on FGF/FGFR inhibition (using receptor inhibitors, ligand traps, monoclonal antibodies, or microRNAs) appear to be extremely promising. However, this approach may lead to further development of resistance through acquisition of specific mutations, metabolism switching, and molecular cross-talks. This review brings together information on the mechanisms underlying the involvement of the FGF/FGFR axis in the generation of drug resistance in cancer and highlights the need for further research to overcome this serious problem with novel therapeutic strategies.

New developments in the biology of fibroblast growth factors

“…Monoclonal antibodies targeting FGFs and FGFRs, ligand traps (soluble FGFR ligand binding domains), small‐molecule FGFR inhibitors, and aptamers are being developed for the treatment of a variety of genetic, metabolic, and oncologic human diseases (Table 2) (Chioni & Grose, 2021; Grabner et al, 2015; Herbert et al, 2014; Ho et al, 2009; Liu et al, 2016; Ornitz & Itoh, 2015; Ornitz & Legeai‐Mallet, 2017; Presta et al, 2017; Szymczyk et al, 2021; Weaver & Bossaer, 2021). Among them, some medications including Burosumab, Erdafitnib, and Pemigatinib have been approved for therapeutic use by the US Food and Drug Administration (FDA).…”

FGF1 protects FGFR1-overexpressing cancer cells against drugs targeting tubulin polymerization by activating AKT via two independent mechanisms

“…There are also reports showing that inhibition of FGFRs by chemical inhibitors (such as PD173074 or BGJ398) in cancer cells increased the cytotoxicity of paclitaxel or vincristine ( 30 – 32 ). Undoubtedly, the actions of FGFs/FGFRs leading to cancer cell resistance include avoidance of apoptosis, EMT, stimulation of angiogenesis, and excessive cell proliferation ( 10 ). However, despite increased research into chemoresistance, the exact mechanisms activated by FGF/FGFR complexes remain unclear.…”

“…FGFR-dependent downstream signaling regulates cell differentiation, migration, apoptosis and the cell cycle, so dysregulation of the FGFR axis often leads to various systemic disorders, including cancers and the development of its drug resistance ( 9 ). The action of FGFs, particularly FGF1 and FGF2, has been correlated with chemoresistance in many types of cancer, but the exact mechanisms have not been fully described ( 10 ). Only a few studies have demonstrated an effect of FGF2 and FGFRs on paclitaxel resistance, but without clearly identifying the specific signaling pathway responsible for this phenomenon ( 11 – 13 ).…”

Inhibition of autophagy potentiates the cytotoxicity of the irreversible FGFR1-4 inhibitor FIIN-2 on lung adenocarcinoma

“…Upon ligand binding, FGFRs autophosphorylate and recruit the critical intracellular adaptor protein FRS2α, leading to the activation of the PI3K/AKT/mTOR and MAPK/ERK pathways [ 7 ]. Aberrant activation of FGFR signalling has been associated with cancer cell proliferation, apoptosis, migration, and platinum resistance in a variety of solid tumours [ 2 , 34 ]. Therefore, FGFR inhibitors are expected to be a new therapeutic option for platinum-resistant LUAD.…”