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Mol Cancer Ther. 2018 Oct;17(10):2217-2225. doi: 10.1158/1535-7163.MCT-17-1022. Epub 2018 Jul 25.

Acquired JHDM1D-BRAF Fusion Confers Resistance to FGFR Inhibition in FGFR2-Amplified Gastric Cancer.

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Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
Contributed equally


FGFR2 gene is frequently amplified in gastric cancer. Recently, targeting FGFR2 has drawn attention as a form of gastric cancer therapy, and FGFR-selective inhibitors have shown promising efficacy in clinical studies. Because overcoming acquired resistance is a common problem with molecular targeting drugs, we investigated a resistant mechanism of FGFR inhibitors using the gastric cancer cell line SNU-16, which harbors FGFR2 amplification. We established single-cell clones of FGFR inhibitor-resistant SNU-16 (AZD-R) by continuous exposure to AZD4547, a selective FGFR inhibitor. To screen the genetic alterations acquired in AZD-R, we ran a comparative genomic hybridization assay and found an amplification of Chr7q34 region. The chromosomal breakpoints were located between the 12th and the 13th exon of jumonji C domain containing histone demethylase 1 homolog D (JHDM1D) and between the 3rd and the 4th exon of BRAF We sequenced cDNA of the AZD-R clones and found fusion kinase JHDM1D-BRAF, which has previously been identified in primary ovarian cancer. Because JHDM1D-BRAF fusion lacks a RAS-binding domain, the dimerization of JHDM1D-BRAF was enhanced. A cell growth inhibition assay using MEK inhibitors and RAF-dimer inhibitors indicated the dependence of AZD-R clones for growth on the MAPK pathway. Our data provide a clinical rationale for using a MEK or RAF dimer inhibitor to treat FGFR2-amplified gastric cancer patients who have acquired resistance through the JHDN1D-BRAF fusion. Mol Cancer Ther; 17(10); 2217-25. ©2018 AACR.

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