Acquired resistance to LY2874455 in FGFR2-amplified gastric cancer through an emergence of novel FGFR2-ACSL5 fusion

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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 and Methods: 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.




Kim, S. Y., Ahn, T., Bang, H., Ham, J. S., Kim, J., Kim, S. T., … Lee, J. (2017). Acquired resistance to LY2874455 in FGFR2-amplified gastric cancer through an emergence of novel FGFR2-ACSL5 fusion. Oncotarget, 8(9), 15014–15022.

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