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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 cancer 1 . However, clinical responses to FGFR inhibitors have remained variable 1–9 , emphasizing the need to better understand...
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Published in: | Nature (London) 2022-08, Vol.608 (7923), p.609-617 |
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Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Abstract
Somatic hotspot mutations and structural amplifications and fusions that affect fibroblast growth factor receptor 2 (encoded by
FGFR2
) occur in multiple types of cancer
1
. However, clinical responses to FGFR inhibitors have remained variable
1–9
, emphasizing the need to better understand which
FGFR2
alterations are oncogenic and therapeutically targetable. Here we apply transposon-based screening
10,11
and tumour modelling in mice
12,13
, 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
(
FGFR2
ΔE18
). Functional in vitro and in vivo examination of a compendium of
FGFR2
ΔE18
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
FGFR2
ΔE18
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. |
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ISSN: | 0028-0836 1476-4687 |
DOI: | 10.1038/s41586-022-05066-5 |