Mol. Cells 2022; 45(11): 789-791
Published online November 7, 2022
https://doi.org/10.14348/molcells.2022.0146
© The Korean Society for Molecular and Cellular Biology
Correspondence to : dpark@ajou.ac.kr
This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.
Targeting fibroblast growth factor receptors (FGFRs) has been slow compared to other targeted cancer therapies for receptor tyrosine kinases, such as epidermal growth factor receptors. The low efficacy and variable response have limited the growth of FGFR inhibitors in clinical use. Nevertheless, recent systematic and genomic approaches have identified the biological conditions for effectively targeting FGFRs and can accelerate the development of targeted drugs. Under clinical and preclinical trials, the inhibitors started fast growing furious races to target FGFRs. Finally, FGFRs will be more actionable and targetable with more precise and effective drugs at the end of the race, passing the finish line.
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
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
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.
Mol. Cells 2022; 45(11): 789-791
Published online November 30, 2022 https://doi.org/10.14348/molcells.2022.0146
Copyright © The Korean Society for Molecular and Cellular Biology.
Department of Molecular Science and Technology, Department of Biological Sciences, Ajou University, Suwon 16499, Korea
Correspondence to:dpark@ajou.ac.kr
This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.
Targeting fibroblast growth factor receptors (FGFRs) has been slow compared to other targeted cancer therapies for receptor tyrosine kinases, such as epidermal growth factor receptors. The low efficacy and variable response have limited the growth of FGFR inhibitors in clinical use. Nevertheless, recent systematic and genomic approaches have identified the biological conditions for effectively targeting FGFRs and can accelerate the development of targeted drugs. Under clinical and preclinical trials, the inhibitors started fast growing furious races to target FGFRs. Finally, FGFRs will be more actionable and targetable with more precise and effective drugs at the end of the race, passing the finish line.
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
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
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.