Receptor tyrosine kinases (RTKs) are popular and prominent targets for cancer drugs. For example, small molecules inhibiting epidermal growth factor receptors (EGFRs), such as osimertinib and imatinib for non-small cell lung cancer and leukemia, respectively, have been blockbuster drugs over the last decades since their approvals. This huge therapeutic success makes sense, as over-expression of the proteins and mutations in the genes are frequent in patient tissues and related to the proliferation of cancer cells across various cancers (Liu et al., 2020). In contrast, the development of drugs targeting fibroblast growth factor receptors (FGFRs), another subfamily of RTKs, has been slowly growing. For instance, the first drug, erdafitinib, was recently approved in 2019 although the genetic and functional significance of FGFRs, such as EGFRs, have been well known. This steady growth is because the efficacy of FGFR inhibitors is low, and clinical responses to the agents are inconsistent (Katoh, 2019). Clues for the clinical variability of the drugs were provided in two recent papers, facilitating the appropriate use of FGFR inhibitors (Chan et al., 2022; Zingg et al., 2022).

The Sawyers group recently reported a study regarding lineage plasticity in prostate cancers that are resistant to antiandrogen using organoid and genetically engineered mouse models (Chan et al., 2022). In this study, the gene expression signatures of epithelial-mesenchymal transition and neuroendocrine prostate cancer (NEPC) were used as representative lineage plasticity phenotypes. It was shown in time-course single-cell RNA sequencing (scRNA-seq) of 67,622 prostate cells from 29 mice bearing adenocarcinoma during transformation to NEPC that the transition was driven by the activation of inflammatory JAK/STAT signals in adenocarcinoma. Based on the scRNA-seq data, the authors calculated per-cell measures of plasticity and then investigated pathways correlated with plasticity. Interestingly, JAK/STAT and FGFR pathways were simultaneously upregulated, as plasticity was induced with the treatment of enzalutamide in the organoids. Both pathways were also activated in patients with castration-resistant prostate cancer samples. Inhibition of the FGFR pathway alone by erdafitinib treatment on fully plastic patient-derived organoids restored only 5%-10% of the organoids to cystic morphology. Surprisingly, hyperplastic morphology was reduced by approximately 10-fold than single inhibition by combinatorial treatment with Jak1/2 kinase inhibitor ruxolitinib. This result suggests that dual inhibition can enhance the reversal of lineage plasticity. Therefore, the inactivation of FGFR signaling would be more effective in consistently inhibiting cancer cell growth in a clinical situation where JAK/STAT pathway is significantly downregulated in tumors.

Zingg et al. (2022) identified a clinically actionable mutation in FGFR2. They performed a transposon-based screening for cancer driver mutations and observed the truncation of exon 18 (E18) at Fgfr2 (Fgfr2ΔE18) in mice. To confirm their findings in human cancers, the authors thoroughly investigated two large-scale cancer genomic data sets: 1) Whole-genome sequencing (WGS) data of Hartwig Medical Foundation and 2) Targeted tumor sequencing data of Foundation Medicine. Eighty-six WGS profiles out of 2,112 showed rearrangement breakpoints at FGFR2 with significant recurrence in intron 17 (I7), which can also generate focal amplification of FGFR2. In addition, analysis of 249,570 targeted sequencing data revealed that 1,367 samples (0.55% incidence) had potential forms of FGFR2ΔE18, including FGFR2-I17/E18 in-frame fusions (55.4%) and various structures of rearrangements (44.6%). The oncogenicity was validated by expressing Fgfr2ΔE18 variants in NMuMG cells, a mouse mammary gland epithelial cell line, and introducing Fgfr2 variants into mouse mammary glands using lentiviruses. Surprisingly, the deletion of E18 played a critical role in oncogenicity, whereas full-length variants marginally affected tumorigenesis. An interesting and brilliant approach to evaluating the targetability of FGFR2ΔE18 in human cancers was to re-analyze clinical trial records of pemigatinib, an FGFR inhibitor approved by the U.S. Food and Drug Administration (FDA) in 2020. Over 80% patients treated with pemigatinib showed either complete response, partial response, or stable disease when they had FGFR2ΔE18 by in-frame fusions or other rearrangements. In contrast, progressive disease was observed in more than 60% patients without FGFR alterations even after pemigatinib treatment, and had the worst prognosis compared to other rearrangement types of FGFR. Therefore, FGFR inhibitors could exhibit stable and high efficacy for patients with specific variants of FGFR: for instance, the variant form with a truncated E18 in this paper.

Until 2021, more than 70 small molecule kinase inhibitors have been FDA-approved as targeted cancer drugs (Ayala-Aguilera et al., 2022). Among them, only three are FGFR-targeting inhibitors that were also recently approved: erdafitinib, pemigatinib, and infigratinib since 2019. However, this is just the beginning. Fast growing furious racing to target FGFRs is highly competitive since there are more than 60 small molecules targeting FGFRs under clinical and preclinical trials (Zheng et al., 2022). For the better use of FGFR inhibitors, two lessons are given to us by the papers reviewed above. First, personalized administration is necessary. Chan et al. (2022) revealed that the absence of JAK/STAT signals could enhance the efficacy of FGFR inhibitors. Thus, systemic diagnostics of signaling pathways using molecular assays and/or multi-omics will help select patients whose cancer cells respond to FGF inhibitors, thereby improving therapeutic outcomes of the targeted subtypes (Heo et al., 2021). Second, the structures of FGFR variants should be considered to obtain consistent clinical outcomes upon treatment with the inhibitors. Since the structural mechanism of FGFRs is complicated and a variety of structural variants occur in cancers, the elucidation of the structures of FGFR variants is critical for properly using inhibitors. At the end of this race, we will eventually make FGFRs more actionable and targetable with more precise and effective drugs on vehicles.

This study was supported by the National Research Foundation, funded by the Ministry of Science and ICT (NRF-2019R1C1C1008181) and the Ministry of Education (NRF-2021R1A6A1A10044950).

The author has no potential conflicts of interest to disclose.