ArticleClinical cancer research : an official journal of the American Association for Cancer Research2024
Understanding and Overcoming Resistance to Selective FGFR Inhibitors across FGFR2-Driven Malignancies.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
18 citing papers in PubMed.
- Recurrent Resistance Mutations to Lirafugratinib Inform Treatment Sequencing in FGFR2-Driven Tumors.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Trial
- Deciphering resistance mechanisms in cancer: final report of MATCH-R study with a focus on molecular drivers and PDX development.Molecular cancer · 2024Trial
- Review
- The role of FGFR signaling in SCLC and NSCLC: Current insights and therapeutic perspectives.iScience · 2026Review
- Sequencing of Fibroblast Growth Factor Receptor Inhibitors in Cholangiocarcinoma: A Review of Published Cases.JCO precision oncology · 2026Review
- VPS33A Promotes Pemigatinib Resistance in Cholangiocarcinoma via Autophagy.Digestive diseases and sciences · 2026Article
- Structure-Based Design and Optimization of Novel, Potent and Selective Covalent FGFR2/3 Inhibitors with a Tricyclic Core.Journal of medicinal chemistry · 2026Article
- The molecular profile of gliomas in adolescents and young adults.Neuro-oncology advances · 2026Review
- FGFR2-Rearranged Biliary Tract Cancer: Biology, Resistance Mechanisms, and Emerging Therapeutic Strategies.Cancers · 2026Review
- FGFR inhibitor resistance in cervical cancer: a role for integrin α2 and mTOR signalling.Frontiers in cell and developmental biology · 2026Article
- mTOR signaling in cholangiocarcinoma: mechanistic insights and therapeutic opportunities.Frontiers in pharmacology · 2026Review
- Saturation mutagenesis identifies activating and resistance-inducing FGFR kinase domain mutations.Nature genetics · 2026Article
- Research on Targeted Therapy for Malignant Tumors of the Biliary Tract.OncoTargets and therapy · 2026Review
- Single-cell multi-omics in biliary tract cancers: decoding heterogeneity, microenvironment, and treatment strategies.Molecular biomedicine · 2025Review
- Lenvatinib after progression on pemigatinib and futibatinib in FGFR2 fusion-positive biliary tract cancer with an acquired kinase point mutation.The oncologist · 2025Article
- Posttranslational modifications of YAP/TAZ: molecular mechanisms and therapeutic opportunities.Cellular & molecular biology letters · 2025Review
- Treating intrahepatic cholangiocarcinoma with pemigatinib: two case reports of Nordic patients.Acta oncologica (Stockholm, Sweden) · 2025Article
- Case Report: FGFR2 inhibitor resistance viaFrontiers in oncology · 2025Article
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Authors and funding
20 authors.
Funding
Abstract
purposeUnderstanding resistance to selective FGFR inhibitors is crucial to improve the clinical outcomes of patients with FGFR2-driven malignancies. EXPERIMENTAL
designWe analyzed sequential ctDNA, ± whole-exome sequencing, or targeted next-generation sequencing on tissue biopsies from patients with tumors harboring activating FGFR2 alterations progressing on pan-FGFR-selective inhibitors, collected in the prospective UNLOCK program. FGFR2::BICC1 Ba/F3 and patient-derived xenograft models were used for functional studies.
resultsThirty-six patients were included. In cholangiocarcinoma, at resistance to both reversible inhibitors (e.g., pemigatinib and erdafitinib) and the irreversible inhibitor futibatinib, polyclonal FGFR2 kinase domain mutations were frequent (14/27 patients). Tumors other than cholangiocarcinoma shared the same mutated FGFR2 residues, but polyclonality was rare (1/9 patients). At resistance to reversible inhibitors, 14 residues in the FGFR2 kinase domain were mutated-after futibatinib, only the molecular brake N550 and the gatekeeper V565. Off-target alterations in PI3K/mTOR and MAPK pathways were found in 11 patients, often together with on-target mutations. At progression to a first FGFR inhibitor, 12 patients received futibatinib or lirafugratinib (irreversible inhibitors), with variable clinical outcomes depending on previous resistance mechanisms. Two patients with TSC1 or PIK3CA mutations benefited from everolimus. In cell viability assays on Ba/F3 and in pharmacologic studies on patient-derived xenografts, irreversible inhibitors retained better activity against FGFR2 kinase domain mutations, with lirafugratinib active against the recalcitrant V565L/F/Y.
conclusionsAt progression to FGFR inhibitors, FGFR2-driven malignancies are characterized by high intra- and interpatient molecular heterogeneity, particularly in cholangiocarcinoma. Resistance to FGFR inhibitors can be overcome by sequential, molecularly oriented treatment strategies across FGFR2-driven tumors.
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