Reference Detail

Ref Type

Journal Article

PMID

(30045926)

Authors

Sase H, Nakanishi Y, Aida S, Horiguchi-Takei K, Akiyama N, Fujii T, Sakata K, Mio T, Aoki M, Ishii N

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	17	10	2018 10	2217-2225	Mol Cancer Ther

URL

Abstract Text

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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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR2 amp	stomach cancer	sensitive	PD173074	Preclinical - Cell culture	Actionable	In a preclinical study, PD173074 inhibited growth of a gastric cancer cell line harboring FGFR2 amplification in culture (PMID: 30045926).	30045926
FGFR2 amp	stomach cancer	sensitive	Infigratinib	Preclinical - Cell culture	Actionable	In a preclinical study, Truseltiq (infigratinib) inhibited growth of a gastric cancer cell line harboring FGFR2 amplification in culture (PMID: 30045926).	30045926
FGFR2 amp	stomach cancer	no benefit	Pictilisib	Preclinical - Cell culture	Actionable	In a preclinical study, a gastric cancer cell line harboring an FGFR2 amplification was not sensitive to Pictilisib (GDC-0941) treatment in culture (PMID: 30045926).	30045926
FGFR2 amp	stomach cancer	no benefit	MK2206	Preclinical - Cell culture	Actionable	In a preclinical study, a gastric cancer cell line harboring an FGFR2 amplification was not sensitive to MK2206 treatment in culture (PMID: 30045926).	30045926
FGFR2 amp	stomach cancer	sensitive	Cediranib	Preclinical - Cell culture	Actionable	In a preclinical study, Cediranib (AZD-2171) inhibited growth of a gastric cancer cell line harboring FGFR2 amplification in culture (PMID: 30045926).	30045926
FGFR2 amp	stomach cancer	sensitive	Fexagratinib	Preclinical - Cell culture	Actionable	In a preclinical study, AZD4547 inhibited growth of a gastric cancer cell line harboring FGFR2 amplification in culture (PMID: 30045926).	30045926