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

Cancer, one of the deadliest and undefeatable diseases, involves the deregulated growth of cells with the conferment of a high potential to metastasize [...].

cellular-trafficking-dependant lysosomal receptor degradation. Interestingly, in some cancers such as biliary tract cancers, FGFR genetic aberrations appear to be the most important predictor of sensitivity to small-molecule TKIs, such as NVP-BGJ398, a pan-FGFR inhibitor [11].
The development of resistance against applied therapeutics is a serious unresolved problem in cancer treatment. Tumour cells may evolve ways to bypass the FGFR-FGF signalling by overexpressing other RTK members (bypass signalling) or by inducing mutations in the inhibitor-binding pocket in the FGFR (gatekeeper mutations) [12]. In these cases, the use of combination therapies and novel FGFR therapies may help in overcoming cancer cell resistance. Moreover, FGFRs, which are not exposed on the cell membrane, may act independently of the tyrosine kinase activity. In fact, FGFRs have been described in several subcellular organelles, such as the endosome, nucleus, and mitochondria. Nuclear and mitochondrial FGFRs are capable of promoting tumourigenesis by modulating gene expression or cellular metabolism. Porębska et al. concisely reviewed how the trafficking of FGFRs can be targeted for selective cancer treatment [2]. As tyrosine kinase activity is not involved, the intracellular FGFRs cannot be targeted using classical anticancer drugs. New strategies aimed at inhibiting the cellular translocation of FGFRs are required. One strategy may involve the selective targeting of the processing proteases present at the plasma membrane [2].
Despite the effort in developing FGFR-pathway-targeting drugs, there are still barriers to their clinical application [13]. Epithelial-to-mesenchymal transition may emerge as a consequence of chronic exposure to FGFR inhibitors, hence resulting in resistance [14]. Additional layers of complication arise from alternative splicing of FGFRs by RNA-binding proteins causing alterations in ligand recognition. For instance, epithelial splicing regulatory factor-1 (ESRP1) was shown to promote the expression of the epithelial isoform of FGFR2, FGFR-2-IIIb (which binds specific ligands of the paracrine FGF family such as FGF-7), at the expense of the mesenchymal isoform FGFR-2-IIIc [3,15]. Both FGFR2 and ESRP1 are frequently amplified and demethylated in gastric cancer, hence leading to increased expression of ESRP1 and the FGFR isoform IIIb [16]. A class switch from FGFR-2-IIIb to FGFR-2-IIIc has been observed during the progression of prostate and bladder cancer, with FGFR-2-IIIc being associated with a more malignant phenotype [17]. Interestingly, restoration of FGFR-2-IIIb in prostate cancer cells enhanced their sensitivity to radiation and chemotherapy, indicating that modulating alternative splicing may be a possible alternative to selectively target the FGFR-FGF pathway [16].
It is becoming increasingly clear that the consequence of FGFR aberrations is not uniform across cancer types. Molecular testing such as next-generation sequencing is employed to analyse tumours to detect actionable FGF/FGFR alterations, but biopsy location and tumour heterogeneity can limit this approach. There is, thus, an urgent need to develop biomarkers to choose the most appropriate treatment strategies and to frequently and non-invasively monitor response to targeted therapies [18]. Analysis of serum or urine circulating tumour DNA, faecal microRNAs, or extracellular vesicles released from tumour cells may overcome these limitations [19][20][21]. Endocrine FGFs may also be applied as serum biomarkers of cancer as recently reviewed in prostate cancer [15]. These data are encouraging and warrant further studies regarding the optimal timing and conditions for measuring these biomolecules.
As phase II clinical trials emerge, patient selection as well as methods for predicting response to therapy and for overcoming toxicity become essential. Future generations of FGFR inhibitors will hopefully overcome current barriers and expedite the availability of these new medications for blocking the progression of cancers that rely on the FGFR-FGF axis [13]. Understanding the FGFR status of tumours, as well as their natural history, molecular mechanisms, prognostic impact, and response to FGFR-targeting is crucial to offer precision-medicine-based therapy for their effective management. Thus, FGFR studies are an excellent example of how in-depth exploration at a molecular level could render the design of individualized therapy plans feasible [22].

Conflicts of Interest:
The authors declare no conflict of interest.