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Activated fibroblast growth factor receptors (FGFRs) frequently drive tumorigenesis by different genetic aberrations. However, it remains unknown which of the many point mutations affecting\n                    <jats:italic>FGFR1<\/jats:italic>\n                    ,\n                    <jats:italic>FGFR2<\/jats:italic>\n                    ,\n                    <jats:italic>FGFR3<\/jats:italic>\n                    or\n                    <jats:italic>FGFR4<\/jats:italic>\n                    in cancer are druggable, that is, activating signaling while not mediating FGFR inhibitor resistance. Here we implemented a saturation mutational scanning platform to screen all 11,520 possible point mutations covering the kinase domains of\n                    <jats:italic>FGFR1<\/jats:italic>\n                    \u2013\n                    <jats:italic>4<\/jats:italic>\n                    . Pooled positive selection screens identified 474 activating and 738 mutations mediating resistance to the FGFR inhibitors pemigatinib and futibatinib, together revealing 301 druggable\n                    <jats:italic>FGFR<\/jats:italic>\n                    mutations analogous to a strong PS3\/BS3 evidence level. The screens also identified loss-of-function mutations and an association of gain-of-function mutations with hydrophobic changes. The functional screens identified 97% of acquired resistance mutations in clinical trials. Our comprehensive catalog of every druggable mutation in the FGFR kinase domains is readily available for clinical decision support.\n                  <\/jats:p>","DOI":"10.1038\/s41588-025-02431-8","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T10:03:50Z","timestamp":1765188230000},"page":"157-168","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Saturation mutagenesis identifies activating and resistance-inducing FGFR kinase domain mutations"],"prefix":"10.1038","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4715-4985","authenticated-orcid":false,"given":"Carla","family":"Tangermann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2172-3791","authenticated-orcid":false,"given":"Avantika","family":"Ghosh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2137-5234","authenticated-orcid":false,"given":"Martin","family":"Ziegler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Facchinetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jannis","family":"Stappenbeck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3881-6140","authenticated-orcid":false,"given":"Yagmur Oyku","family":"Carus Sahin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4178-1685","authenticated-orcid":false,"given":"Marisa","family":"Riester","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luise Carmina","family":"Viardot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Zundel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc","family":"Friboulet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoine","family":"Hollebecque","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8640-6690","authenticated-orcid":false,"given":"Jos\u00e9 J.","family":"Naveja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Wanninger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5792-3657","authenticated-orcid":false,"given":"Maria Elena","family":"Hess","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4387-7905","authenticated-orcid":false,"given":"Tilman","family":"Brummer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3670-0602","authenticated-orcid":false,"given":"Melanie","family":"Boerries","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Loges","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8338-1739","authenticated-orcid":false,"given":"Yohann","family":"Loriot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna L.","family":"Illert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7901-4752","authenticated-orcid":false,"given":"Sven","family":"Diederichs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"key":"2431_CR1","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1038\/s41586-018-0461-z","volume":"562","author":"GM Findlay","year":"2018","unstructured":"Findlay, G. 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L.F. received research funding from Debiopharm, Incyte, Relay Therapeutics, Sanofi and Nuvalent. A.H. received honoraria from Amgen, AstraZeneca, Debiopharm, Eli Lilly and Company, Incyte Corporation and QED Therapeutics. T.B. received honoraria from Pierre Fabre and the European Society for Medical Oncology for activities unrelated to the content of this paper. S.L. has an advisory role at Lilly, Sanofi, BerGenBio, Novartis, Boehringer Ingelheim, BMS, Roche, AstraZeneca, MSD, Merck, Sanofi-Aventis, Janssen, Takeda, Pfizer, Amgen, Bayer, Medac and Daiichi-Sankyo, and received honoraria and payments for travel costs from Lilly, Sanofi, BerGenBio, Novartis, Boehringer Ingelheim, BMS, Roche, AstraZeneca, MSD, Merck, Sanofi-Aventis, Janssen, Takeda, Pfizer, Amgen, Bayer, Medac and Daiichi-Sankyo. In addition, research grants were obtained from Roche, BerGenBio, Lilly, ADC Therapeutics and Daiichi-Sankyo. Y.L. received honoraria from AstraZeneca, Astellas, BMS, Gilead, Janssen, Merck KGaA, MSD and Pfizer, and received payments for travel and accommodation from Astellas, BMS, Janssen, Merck KGaA, MSD, Pfizer and Roche. A.L.I. has an advisory role for Bayer, Takeda, Janssen, Roche, AbbVie and Fido, and has given lectures for Sodi, Takeda, Roche, Amgen, Janssen, AbbVie, FOMF and Illumina. S.D. receives research funding from BioMarin and is a co-owner of siTOOLs Biotech, Martinsried, Germany, unrelated to this work. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}