FGFR-TKI resistance in cancer: current status and perspectives

Abstract

Fibroblast growth factor receptors (FGFRs) play key roles in promoting the proliferation, differentiation, and migration of cancer cell. Inactivation of FGFRs by tyrosine kinase inhibitors (TKI) has achieved great success in tumor-targeted therapy. However, resistance to FGFR-TKI has become a concern. Here, we review the mechanisms of FGFR-TKI resistance in cancer, including gatekeeper mutations, alternative signaling pathway activation, lysosome-mediated TKI sequestration, and gene fusion. In addition, we summarize strategies to overcome resistance, including developing covalent inhibitors, developing dual-target inhibitors, adopting combination therapy, and targeting lysosomes, which will facilitate the transition to precision medicine and individualized treatment.

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

“…Deregulated metabolism can drive further mutations (e.g., gatekeeper mutations in kinase domain of FGFR) leading to cross-resistance and thus to the ineffectiveness of even the most specialized strategies [ 195 , 196 , 226 , 227 , 228 ]. On the other hand, reports of positive effects of FGF/FGFR on chemotherapy further emphasize the complexity of the whole system [ 246 , 247 , 248 ].…”

“…In recent years, tremendous progress has been made in modulating or correcting aberrant FGF/FGFR signaling [ 12 , 105 , 194 , 195 ]. Such a strategy includes the application of receptor inhibitors, ligand traps, monoclonal antibodies, microRNAs, and combination therapy ( Figure 4 ) [ 12 , 105 , 194 , 195 , 196 ].…”

“…Currently, some TKIs have been developed to inhibit FGFR, that can be divided into two groups: (i) non-selective FGFR TKIs, targeting a wide range of tyrosine kinases, including FGFR, and (ii) selective FGFR TKIs, targeting specifically the FGFR group ( Table 2 ) [ 194 , 195 , 196 , 197 ]. AZD4547, as an example of the second group, exhibits pro-apoptotic and anti-proliferative activity in cell lines with deregulated FGFR expression, such as KG1a (acute myeloid leukemia line), Sum52-PE (breast cancer cell line), and KMS11 (multiple myeloma line) [ 198 ].…”

“…Clinical trials have shown that a significant fraction of patients with FGFR-positive tumors do not respond to treatment with FGFRs inhibitors [ 224 , 225 ]. Mutations located in ATP-binding sites of the kinase domain of FGFR have been shown to be a common cause of inhibitor resistance in FGFR-dependent tumors, especially gatekeeper mutation resulting in increased receptor activity [ 195 , 196 , 226 , 227 , 228 ]. Generated gatekeeper FGFR3-V555M mutation in KMS-11 myeloma cells with acquired resistance to AZ12908010 caused cross-resistance to two other FGFR inhibitors, AZD4547 and PD173074 [ 227 ].…”

Systemic Analysis of the DNA Replication Regulator MCM Complex in Ovarian Cancer and Its Prognostic Value

“…Inhibition of cancer-promoting kinases has been considered to be an established therapeutic strategy for treating many cancer types ( 52 ). In our previous study, FGFR tyrosine kinase inhibitors (TKIs) were shown to repress the proliferation, differentiation, and migration of cancer cells, showing that they have great potential for development in precision medicine and individualized treatment of cancer patients ( 53 ). Therefore, further research on the development of post-translational modifications and, in particular, kinase inhibitors targeting the MCM complex would be beneficial for cancer treatment.…”