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

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.

• Authors: Sun Young Kim, Taejin Ahn, Heejin Bang, Jun Soo Ham, Jusun Kim, Seung Tae Kim, Jiryeon Jang, Moonhee Shim, So Young Kang, Se Hoon Park, Byung Hoon Min, Hyuk Lee, Won Ki Kang, Kyoung-Mee Kim, Woongyang Park, Jeeyun Lee
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 9 Pg. 15014-15022 (Feb 28 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28122360 (Publication Type: Case Reports, Journal Article)

Chemical References

• 2-(4-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3yl)vinyl)-1H-pyrazol-1-yl)ethanol
• Indazoles
• Oncogene Proteins, Fusion
• FGFR2 protein, human
• Receptor, Fibroblast Growth Factor, Type 2
• Coenzyme A Ligases
• ACSL5 protein, human

Topics

• Adult
• Coenzyme A Ligases (genetics)
• Drug Resistance, Neoplasm (genetics)
• Female
• Gene Amplification
• Humans
• Indazoles (pharmacology)
• Oncogene Proteins, Fusion (genetics)
• Prognosis
• Receptor, Fibroblast Growth Factor, Type 2 (genetics)
• Stomach Neoplasms (drug therapy, genetics, pathology)