Abstract
Simple SummaryDeregulation of the FGF/FGFR axis is associated with many types of cancer and contributes to the development of chemoresistance, limiting the effectiveness of current treatment strategies. There are several mechanisms involved in this phenomenon, including cross-talks with other signaling pathways, avoidance of apoptosis, stimulation of angiogenesis, and initiation of EMT. Here, we provide an overview of current research and approaches focusing on targeting components of the FGFR/FGF signaling module to overcome drug resistance during anti-cancer therapy.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.
Highlights
The development of resistance to pharmaceutical treatment is a common problem that affects a broad spectrum of diseases, in particular cancer
In colorectal cancer (CRC), the FGFR2/JAK/STAT3 pathway promotes the expression of programmed cell death ligand 1 (PD-L1), a transmembrane protein associated with reduced T-cell proliferation [98]
Another study showed that TGFβ and FGF2 efficiently induced epithelial-to-mesenchymal transition (EMT) in human lung adenocarcinoma cell lines: in PC-9 cells via the Smad3 pathway, and in hepatocellular carcinoma (HCC)-827 cells through Smad3, MEK/ERK, and mTOR pathways resulting in reduced sensitivity to gefitinib in both cell lines and to cisplatin only in HCC-827 cells (Figure 3) [81]
Summary
The development of resistance to pharmaceutical treatment is a common problem that affects a broad spectrum of diseases, in particular cancer. A large range of mechanisms potentially involved in the emergence of chemoresistance exists, which severely hinders overcoming this problem These mechanisms, often arising from DNA mutations and metabolism switching, include expression of efflux cell membrane transporters, drug inactivation, alteration in drug molecular targets, enhancing DNA repair machinery, epithelial-to-mesenchymal transition (EMT), or inhibition of apoptosis [1,3]. Another aspect is the diverse tumor microenvironment and heterogeneity of cancer cells, characterized by the formation of many subpopulations of cells with different drug sensitivity and the evolution of resistant clones [2]. The relationship between the action of FGF/FGFR and the occurrence of drug resistance in cancer cells is presented and their specific mechanisms of action are proposed to be considered as targets for cancer treatment
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
