Journal article
Truncated FGFR2 is a clinically actionable oncogene in multiple cancers
- Abstract:
- Somatic 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 variable1,2,3,4,5,6,7,8,9, 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
Actions
Access Document
- Files:
-
-
(Preview, Version of record, pdf, 62.8MB, Terms of use)
-
- Publisher copy:
- 10.1038/s41586-022-05066-5
Authors
- Publisher:
- Springer Nature
- Journal:
- Nature More from this journal
- Volume:
- 608
- Issue:
- 7923
- Pages:
- 609–617
- Place of publication:
- England
- Publication date:
- 2022-08-10
- Acceptance date:
- 2022-07-03
- DOI:
- EISSN:
-
1476-4687
- ISSN:
-
0028-0836
- Pmid:
-
35948633
- Language:
-
English
- Keywords:
- Subjects:
- Pubs id:
-
1275498
- Local pid:
-
pubs:1275498
- Deposit date:
-
2023-04-19
- ARK identifier:
Terms of use
- Copyright holder:
- Zingg et al.
- Copyright date:
- 2022
- Rights statement:
- © The Author(s) 2022, corrected publication 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
- Notes:
- A Publisher Correction to this article was published on 01 September 2022. See https://doi.org/10.1038/s41586-022-05287-8.
- Licence:
- CC Attribution (CC BY)
If you are the owner of this record, you can report an update to it here: Report update to this record