In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 3488-3488
Abstract:
Human cancers frequently bear driver alterations in genes encoding receptor tyrosine kinases (RTKs), which has led to effective therapeutics targeting oncogenic signaling of RTK variants. Somatic hotspot mutations and structural amplifications and fusions affecting fibroblast growth factor receptor 2 (FGFR2) likewise occur in multiple tumor types including breast cancer. However, clinical responses to FGFR inhibitors have remained variable, emphasizing a need to better understand which FGFR2 alterations are oncogenic and therapeutically targetable. We applied transposon-based screening and tumor modelling in the mouse mammary gland to uncover truncation of the last exon (E18) of Fgfr2 as a potent driver mutation. Mouse and human FGFR2-E18 encodes the C-terminus of this RTK. Human oncogenomic datasets revealed a plethora of somatic FGFR2 alterations potentially causing transcription of E18-truncated FGFR2. These alterations were comprised of canonical in-frame fusions as well as diverse FGFR2 variants of unknown significance (VUS), which included non-canonical rearrangements, E1-E17 partial amplifications, and E18 nonsense and frameshift mutations. Functional in vitro and in vivo interrogation of a compendium of E18-truncated and full-length FGFR2 variants pinpointed FGFR2-E18 truncation as single-driver alteration in cancer. In contrast, the oncogenic competence of FGFR2 full-length amplifications depended on a distinct cooperating driver gene landscape. Notably, gradual truncation and site-directed mutagenesis of Fgfr2-E18 identified a novel 2-amino-acid motif within the C-terminus critical for kinase domain binding and suppression of oncogenic FGFR2 signaling. Aberration of this motif conspired with the loss of the receptor internalization motif to fully phenocopy oncogenicity of E18-truncated Fgfr2. These data suggest that genomic alterations that generate stable E18-truncated FGFR2 variants are actionable therapeutic targets, which we confirmed in preclinical mouse and human tumor models, and in a clinical trial. Thus, we uncovered a novel paradigm in oncogenic FGFR2 signaling and propose that breast and other cancers harboring any FGFR2 variant that truncates E18 should be considered for FGFR-targeted therapies. Citation Format: Daniel Kaspar Zingg, Jinhyuk Bhin, Julia Yemelyanenko, Sjors M. Kas, Catrin Lutz, Chi-Chuan Lin, Sjoerd Klarenbeek, Jessica K. Lee, Ian M. Silverman, Stefano Annunziato, Marieke van de Ven, Siraj M. Ali, Timothy C. Burn, Shridar Ganesan, Lodewyk F. Wessels, Jos Jonkers. Truncated FGFR2 - a clinically actionable oncogene in multiple cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3488.
Type of Medium:
Online Resource
ISSN:
1538-7445
DOI:
10.1158/1538-7445.AM2023-3488
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2023
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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