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 variable1–9, 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.

Multi-omics analysis reveals distinct non-reversion mechanisms of PARPi resistance in BRCA1- versus BRCA2-deficient mammary tumors

“…For the proteomic and phosphoproteomic analyses of KB1P(M) tumors, we used previously published proteomics dataset generated by MS (PRIDE accession code: PXD032007) (Zingg et al, 2022). For phosphoproteomic analysis, For phosphoproteomic analysis, MaxQuant phosphosite quantification data (Phospho (STY)Sites.txt) was log2-transformed, normalized on the median intensity of all identified phosphosites and replicates averaged favoring data presence.…”

Taraxasterol suppresses the proliferation and tumor growth of prostate cancer cells through the FGFR2-PI3K/AKT signaling pathway

“…Moreover, PTEN deletion activates the PI3K/AKT/mTOR pathway, which is the most common molecular mechanism of CRPC and one of the causes of ADT resistance 18 . Fibroblast growth factor receptor 2 (FGFR2), has often happened somatic hotspot mutations, structural ampli cation and fusion in multiple cancers 19 . A previous study found that the loss of FGFR2 is related to the malignant progression of prostate cancer and it will be a clinical therapeutic target 20 .…”

Fast Growing Furious Races for Targeting Fibroblast Growth Factor Receptors

“…Therefore, the inactivation of FGFR signaling would be more effective in consistently inhibiting cancer cell growth in a clinical situation where JAK/STAT pathway is significantly downregulated in tumors. Zingg et al (2022) identified a clinically actionable mutation in FGFR2. They performed a transposon-based screening for cancer driver mutations and observed the truncation of exon 18 (E18) at Fgfr2 (Fgfr2 ΔE18 ) in mice.…”

“…This steady growth is because the efficacy of FGFR inhibitors is low, and clinical responses to the agents are inconsistent ( Katoh, 2019 ). Clues for the clinical variability of the drugs were provided in two recent papers, facilitating the appropriate use of FGFR inhibitors ( Chan et al, 2022 ; Zingg et al, 2022 ).…”

“… Zingg et al (2022) identified a clinically actionable mutation in FGFR2. They performed a transposon-based screening for cancer driver mutations and observed the truncation of exon 18 (E18) at Fgfr2 ( Fgfr2ΔE18 ) in mice.…”