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

Abstract

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 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 () and between the 3rd and the 4th exon of We sequenced cDNA of the AZD-R clones and found fusion kinase, 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 -amplified gastric cancer patients who have acquired resistance through the JHDN1D-BRAF fusion..

FGFR2-Altered Gastroesophageal Adenocarcinomas Are an Uncommon Clinicopathologic Entity with a Distinct Genomic Landscape

“…Similarly, FGFR2 amplification has been observed as an infrequent mechanism of trastuzumab resistance, and “contamination” from post‐trastuzumab samples is not expected to play a major role in our findings . Furthermore, we did not observe prior mechanisms of FGFR2 inhibitor resistance among our samples, adding further indirect support that we are representing an FGFR2‐directed‐therapy‐naive population . Although prior publication has suggested HER2 by IHC may be altered by chemoradiotherapy, it is less clear if this applies when the alteration is defined genomically .…”

Mechanisms of acquired resistance to fibroblast growth factor receptor targeted therapy

“…Bypass signaling can also occur due to changes within the PI3K/AKT/mTOR [55][56][57] , MAPK [50,58,59] , STAT3 [60] and GSK3β [61] signaling pathways. Increased PI3K/AKT/mTOR signaling, independent of changes in upstream receptor tyrosine kinases has been described in DMS114 lung cancer cells (FGFR1 amplified) and RT112 urothelial cancer cells (FGFR3-TACC3) following chronic treatment with infigratinib [56] .…”

“…MAPK activation in FGFR1 amplified lines is shown to be mediated by a secondary mutation in NRAS [59] and through C. Activation of intracellular signaling pathways chromosomal arm loss on chromosome 12p resulting in downregulation of DUSP6 [50] a negative regulator of the MAPK pathway. Alternatively, in FGFR2 amplified cells constitutive MAPK signaling was mediated through the emergence of the BRAF fusion kinase JHM1D-BRAF which is demonstrated to enhance the dimerization capacity of BRAF [58] .…”

Next-generation sequencing and biomarkers for gastric cancer: what is the future?

“…Furthermore, JHDM1D–BRAF fusion results in resistance for FGFR inhibitor-resistant cell line, which warrants further research. 52,53…”