FGFR-TKI resistance in cancer: current status and perspectives

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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.

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Most cited references 128

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Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study

Ghassan Abou-Alfa, Vaibhav Sahai, Antoine Hollebecque … (2020)

Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements.

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Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma

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Fibroblast growth factor signalling: from development to cancer.

Nicholas Turner, Richard P Grose (2010)

Fibroblast growth factors (FGFs) and their receptors control a wide range of biological functions, regulating cellular proliferation, survival, migration and differentiation. Although targeting FGF signalling as a cancer therapeutic target has lagged behind that of other receptor tyrosine kinases, there is now substantial evidence for the importance of FGF signalling in the pathogenesis of diverse tumour types, and clinical reagents that specifically target the FGFs or FGF receptors are being developed. Although FGF signalling can drive tumorigenesis, in different contexts FGF signalling can mediate tumour protective functions; the identification of the mechanisms that underlie these differential effects will be important to understand how FGF signalling can be most appropriately therapeutically targeted.

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Author and article information

Contributors

Yongheng Chen: yonghenc@163.com

Daichao Wu:

ORCID: http://orcid.org/0000-0003-2086-0190

wudc_lab@163.com , wudc@umd.edu

Journal

Journal ID (nlm-ta): J Hematol Oncol

Journal ID (iso-abbrev): J Hematol Oncol

Title: Journal of Hematology & Oncology

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-8722

Publication date (Electronic): 10 February 2021

Publication date PMC-release: 10 February 2021

Publication date Collection: 2021

Volume: 14

Electronic Location Identifier: 23

Affiliations

[1 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Oncology, Laboratory of Structural Biology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, , Central South University, ; Changsha, 410008 Hunan China

[2 ]GRID grid.412017.1, ISNI 0000 0001 0266 8918, Clinical Anatomy and Reproductive Medicine Application Institute, Department of Histology and Embryology, Hunan Province Key Laboratory of Cancer Cellular and Molecular Pathology, , University of South China, ; Hengyang, 421001 China

[3 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, , Central South University, ; Changsha Hunan, 410008 China

[4 ]GRID grid.440664.4, ISNI 0000 0001 0313 4029, W.M. Keck Laboratory for Structural Biology, , University of Maryland Institute for Bioscience and Biotechnology Research, ; Rockville, MD 20850 USA

Author information

Daichao Wu http://orcid.org/0000-0003-2086-0190

Article

Publisher ID: 1040

DOI: 10.1186/s13045-021-01040-2

PMC ID: 7876795

PubMed ID: 33568192

SO-VID: 95fe2018-e0a5-4f81-a2e5-a192e40218c6

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 29 October 2020

Date accepted : 1 February 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81974074 and 81570537

Award Recipient : Yongheng Chen

Funded by: Outstanding Youth Project of Hunan Education Department

Award ID: 19B475

Award Recipient : Daichao Wu

Funded by: Open Project of State Local Joint Engineering Laboratory for Anticancer Drugs

Award ID: KAYW-FK-20-01

Award Recipient : Daichao Wu

Funded by: Scientific Research Foundation of the University of South China

Award ID: 190XQD016

Award Recipient : Daichao Wu

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: fgfr,tyrosine kinase inhibitor,drug resistance,gatekeeper mutation,lysosome sequestration

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: fgfr, tyrosine kinase inhibitor, drug resistance, gatekeeper mutation, lysosome sequestration

FGFR-TKI resistance in cancer: current status and perspectives

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Karger: Oncology

Most cited references 128

Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study

Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma

Fibroblast growth factor signalling: from development to cancer.

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