ArticleACS chemical biology2015
Illuminating the molecular mechanisms of tyrosine kinase inhibitor resistance for the FGFR1 gatekeeper mutation: the Achilles' heel of targeted therapy.
Article in ACS chemical biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 70 citations in OpenAlex.
- Advances in the design and discovery of small-molecule tyrosine kinase inhibitors for breast cancer.RSC advances · 2026Review
- Pharmacological and Biological Targeting of FGFR1 in Cancer.Current issues in molecular biology · 2024Review
- Clinical advances and challenges in targeting FGF/FGFR signaling in lung cancer.Molecular cancer · 2024Review
- Targeting FGFR for cancer therapy.Journal of hematology & oncology · 2024Review
- Discovery of lirafugratinib (RLY-4008), a highly selective irreversible small-molecule inhibitor of FGFR2.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Structural basis and selectivity of sulfatinib binding to FGFR and CSF-1R.Communications chemistry · 2024Article
- ATF4 renders human T-cell acute lymphoblastic leukemia cell resistance to FGFR1 inhibitors through amino acid metabolic reprogramming.Acta pharmacologica Sinica · 2023Article
- Review
- Biological and clinical implications of FGFR aberrations in paediatric and young adult cancers.Oncogene · 2023Review
- Gatekeeper mutations activate FGF receptor tyrosine kinases by destabilizing the autoinhibited state.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Preclinical characterization of CPL304110 as a potent and selective inhibitor of fibroblast growth factor receptors 1, 2, and 3 for gastric, bladder, and squamous cell lung cancer.Frontiers in oncology · 2023Article
- Characterization of the cholangiocarcinoma drug pemigatinib against FGFR gatekeeper mutants.Communications chemistry · 2022Article
- Futibatinib, an Irreversible FGFR1-4 Inhibitor, in Patients with Advanced Solid Tumors HarboringCancer discovery · 2022Article
- Signaling Pathway and Small-Molecule Drug Discovery of FGFR: A Comprehensive Review.Frontiers in chemistry · 2022Review
- GZD824 overcomes FGFR1-V561F/M mutant resistance in vitro and in vivo.Cancer medicine · 2021Article
- Review
- FGFR-TKI resistance in cancer: current status and perspectives.Journal of hematology & oncology · 2021Review
- Dual activating FGFR1 mutations in pediatric pilomyxoid astrocytoma.Molecular genetics & genomic medicine · 2021Article
- Mechanisms of resistance to FGFR1 inhibitors in FGFR1-driven leukemias and lymphomas: implications for optimized treatment.Cancer drug resistance (Alhambra, Calif.) · 2021Article
- FGF/FGFR signaling in health and disease.Signal transduction and targeted therapy · 2020Review
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Human fibroblast growth factor receptors (FGFRs) 1-4 are a family of receptor tyrosine kinases that can serve as drivers of tumorigenesis. In particular, FGFR1 gene amplification has been implicated in squamous cell lung and breast cancers. Tyrosine kinase inhibitors (TKIs) targeting FGFR1, including AZD4547 and E3810 (Lucitanib), are currently in early phase clinical trials. Unfortunately, drug resistance limits the long-term success of TKIs, with mutations at the "gatekeeper" residue leading to tumor progression. Here we show the first structural and kinetic characterization of the FGFR1 gatekeeper mutation, V561M FGFR1. The V561M mutation confers a 38-fold increase in autophosphorylation achieved at least in part by a network of interacting residues forming a hydrophobic spine to stabilize the active conformation. Moreover, kinetic assays established that the V561M mutation confers significant resistance to E3810, while retaining affinity for AZD4547. Structural analyses of these TKIs with wild type (WT) and gatekeeper mutant forms of FGFR1 offer clues to developing inhibitors that maintain potency against gatekeeper mutations. We show that AZD4547 affinity is preserved by V561M FGFR1 due to a flexible linker that allows multiple inhibitor binding modes. This is the first example of a TKI binding in distinct conformations to WT and gatekeeper mutant forms of FGFR, highlighting adaptable regions in both the inhibitor and binding pocket crucial for drug design. Exploiting inhibitor flexibility to overcome drug resistance has been a successful strategy for combatting diseases such as AIDS and may be an important approach for designing inhibitors effective against kinase gatekeeper mutations.
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