Acquired resistance to LY2874455 in FGFR2-amplified gastric cancer through an emergence of novel FGFR2-ACSL5 fusion.
Oncotarget
; 8(9): 15014-15022, 2017 Feb 28.
Article
em En
| MEDLINE
| ID: mdl-28122360
ABSTRACT
BACKGROUND:
Fibroblast growth factor 2 (FGFR2) amplification, occurring in ~2-9% of gastric cancers (GC), is associated with poor overall survival.RESULTS:
RNA sequencing identified a novel FGFR2-ACSL5 fusion in the resistant tumor that was absent from the matched pre-treatment tumor. The FGFR2-amplified PDC line was sensitive to FGFR inhibitors whereas the PDC line with concomitant FGFR2 amplification and FGFR2-ACSL5 fusion exhibited resistance. Additionally, the FGFR2-amplified GC PDC line, which was initially sensitive to FGFR2 inhibitors, subsequently also developed resistance. MATERIALS ANDMETHODS:
We identified an FGFR2-amplified patient with GC, who demonstrated a dramatic and long-term response to LY2874455, a pan-FGFR inhibitor, but eventually developed an acquired LY2874455 resistance. Following resistance development, an endoscopic biopsy was performed for transcriptome sequencing and patient-derived tumor cell line (PDC) establishment to elucidate the underlying molecular alterations.CONCLUSIONS:
FGFR inhibitors may function against FGFR2-amplified GC, and a novel FGFR2-ACSL5 fusion identified by transcriptomic characterization may underlie clinically acquired resistance. IMPLICATIONS FOR PRACTICE Poor treatment response represents a substantial concern in patients with gastric cancer carrying multiple FGFR2 gene copies. Here, we show the utility of a general FGFR inhibitor for initial response prior to treatment resistance and report the first characterization of a potential resistance mechanism involving an FGFR2-ACSL5 fusion protein.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Gástricas
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Proteínas de Fusão Oncogênica
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Amplificação de Genes
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Coenzima A Ligases
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Resistencia a Medicamentos Antineoplásicos
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Receptor Tipo 2 de Fator de Crescimento de Fibroblastos
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Indazóis
Tipo de estudo:
Prognostic_studies
Limite:
Adult
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Female
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Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article