title: Landscape of activating cancer mutations in FGFR kinases and their differential responses to inhibitors in clinical use.
abstract: Frequent genetic alterations discovered in FGFRs and evidence implicating some as drivers in diverse tumors has been accompanied by rapid progress in targeting FGFRs for anticancer treatments. Wider assessment of the impact of genetic changes on the activation state and drug responses is needed to better link the genomic data and treatment options. We here apply a direct comparative and comprehensive analysis of FGFR3 kinase domain variants representing the diversity of point-mutations reported in this domain. We reinforce the importance of N540K and K650E and establish that not all highly activating mutations (for example R669G) occur at high-frequency and conversely, that some "hotspots" may not be linked to activation. Further structural characterization consolidates a mechanistic view of FGFR kinase activation and extends insights into drug binding. Importantly, using several inhibitors of particular clinical interest (AZD4547, BGJ-398, TKI258, JNJ42756493 and AP24534), we find that some activating mutations (including different replacements of the same residue) result in distinct changes in their efficacy. Considering that there is no approved inhibitor for anticancer treatments based on FGFR-targeting, this information will be immediately translatable to ongoing clinical trials.
authors.affiliation: Institute of Structural and Molecular Biology, Division of Biosciences, University College London, Gower St, London WC1E 6BT, UK.
authors.forename: Harshnira
authors.initials: H
authors.lastname: Patani
authors.affiliation: Institute of Structural and Molecular Biology, Division of Biosciences, University College London, Gower St, London WC1E 6BT, UK.
authors.forename: Tom D
authors.initials: TD
authors.lastname: Bunney
authors.affiliation: Institute of Structural and Molecular Biology, Division of Biosciences, University College London, Gower St, London WC1E 6BT, UK.
authors.forename: Nethaji
authors.initials: N
authors.lastname: Thiyagarajan
authors.affiliation: Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Norman
authors.affiliation: Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Derek
authors.initials: D
authors.lastname: Ogg
authors.affiliation: Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Jason
authors.initials: J
authors.lastname: Breed
authors.affiliation: Institute of Structural and Molecular Biology, Division of Biosciences, University College London, Gower St, London WC1E 6BT, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Ashford
authors.affiliation: Institute of Structural and Molecular Biology, Division of Biosciences, University College London, Gower St, London WC1E 6BT, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Potterton
authors.affiliation: Institute of Structural and Molecular Biology, Division of Biosciences, University College London, Gower St, London WC1E 6BT, UK.
authors.forename: Mina
authors.initials: M
authors.lastname: Edwards
authors.affiliation: Section of Experimental Oncology, Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Sarah V
authors.initials: SV
authors.lastname: Williams
authors.affiliation: Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Thomson
authors.affiliation: Institute of Structural and Molecular Biology, Division of Biosciences, University College London, Gower St, London WC1E 6BT, UK.
authors.forename: Camilla S M
authors.initials: CS
authors.lastname: Pang
authors.affiliation: Section of Experimental Oncology, Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Knowles
authors.affiliation: Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Breeze
authors.affiliation: Institute of Structural and Molecular Biology, Division of Biosciences, University College London, Gower St, London WC1E 6BT, UK.
authors.forename: Christine
authors.initials: C
authors.lastname: Orengo
authors.affiliation: Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Phillips
authors.affiliation: Institute of Structural and Molecular Biology, Division of Biosciences, University College London, Gower St, London WC1E 6BT, UK.
authors.forename: Matilda
authors.initials: M
authors.lastname: Katan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000473:pathology*; D006801:Humans; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C572463:AZD4547; D000970:Antineoplastic Agents; D001549:Benzamides; D014408:Biomarkers, Tumor; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3
keywords: cancer mutations; precision medicine; receptor tyrosine kinases; resistance; small molecule inhibitors