Research Papers:
Acquired resistance to LY2874455 in FGFR2-amplified gastric cancer through an emergence of novel FGFR2-ACSL5 fusion
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Abstract
Sun Young Kim1,*, Taejin Ahn2,* Heejin Bang3,* Jun Soo Ham1, Jusun Kim1, Seung Tae Kim1, Jiryeon Jang1, Moonhee Shim1, So Young Kang3, Se Hoon Park1, Byung Hoon Min4, Hyuk Lee4, Won Ki Kang1, Kyoung-Mee Kim3, Woongyang Park2,5, Jeeyun Lee1
1Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
2Samsung Genome Institute, Seoul, Korea
3Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
4Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
5Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Seoul, Korea
*These authors are contributed equally to this work
Correspondence to:
Jeeyun Lee, email: [email protected]
Keywords: gastric cancer, FGFR2 amplification, targeted therapy
Received: October 17, 2016 Accepted: January 11, 2017 Published: January 21, 2017
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 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.
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