Truncated FGFR2 is a clinically actionable oncogene in multiple cancers
Author:
Zingg DanielORCID, Bhin JinhyukORCID, Yemelyanenko JuliaORCID, Kas Sjors M., Rolfs Frank, Lutz Catrin, Lee Jessica K.ORCID, Klarenbeek SjoerdORCID, Silverman Ian M.ORCID, Annunziato Stefano, Chan Chang S.ORCID, Piersma Sander R., Eijkman Timo, Badoux Madelon, Gogola Ewa, Siteur Bjørn, Sprengers Justin, de Klein Bim, de Goeij-de Haas Richard R., Riedlinger Gregory M., Ke Hua, Madison RussellORCID, Drenth Anne Paulien, van der Burg Eline, Schut Eva, Henneman Linda, van Miltenburg Martine H., Proost Natalie, Zhen Huiling, Wientjens Ellen, de Bruijn Roebi, de Ruiter Julian R., Boon Ute, de Korte-Grimmerink Renske, van Gerwen Bastiaan, Féliz LuisORCID, Abou-Alfa Ghassan K., Ross Jeffrey S., van de Ven Marieke, Rottenberg SvenORCID, Cuppen Edwin, Chessex Anne Vaslin, Ali Siraj M.ORCID, Burn Timothy C.ORCID, Jimenez Connie R., Ganesan Shridar, Wessels Lodewyk F. A.ORCID, Jonkers JosORCID
Abstract
AbstractSomatic hotspot mutations and structural amplifications and fusions that affect fibroblast growth factor receptor 2 (encoded by FGFR2) occur in multiple types of cancer1. However, clinical responses to FGFR inhibitors have remained variable1–9, emphasizing the need to better understand which FGFR2 alterations are oncogenic and therapeutically targetable. Here we apply transposon-based screening10,11 and tumour modelling in mice12,13, and find that the truncation of exon 18 (E18) of Fgfr2 is a potent driver mutation. Human oncogenomic datasets revealed a diverse set of FGFR2 alterations, including rearrangements, E1–E17 partial amplifications, and E18 nonsense and frameshift mutations, each causing the transcription of E18-truncated FGFR2 (FGFR2ΔE18). Functional in vitro and in vivo examination of a compendium of FGFR2ΔE18 and full-length variants pinpointed FGFR2-E18 truncation as single-driver alteration in cancer. By contrast, the oncogenic competence of FGFR2 full-length amplifications depended on a distinct landscape of cooperating driver genes. This suggests that genomic alterations that generate stable FGFR2ΔE18 variants are actionable therapeutic targets, which we confirmed in preclinical mouse and human tumour models, and in a clinical trial. We propose that cancers containing any FGFR2 variant with a truncated E18 should be considered for FGFR-targeted therapies.
Publisher
Springer Science and Business Media LLC
Subject
Multidisciplinary
Reference112 articles.
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