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Ref Type Journal Article
PMID (26294741)
Authors Kwak Y, Cho H, Hur W, Sim T
Title Antitumor Effects and Mechanisms of AZD4547 on FGFR2-Deregulated Endometrial Cancer Cells.
Journal Molecular cancer therapeutics
Vol 14
Issue 10
Date 2015 Oct
URL
Abstract Text Uncontrolled activation of FGFRs induces the progression of various cancers. It was recently reported that FGFR2-activating mutants are implicated in about 12% of endometrial carcinomas. AZD4547, a potent pan-FGFR inhibitor, is currently being evaluated in clinical trials for several FGFR-driven cancers. However, AZD4547 has not been examined yet against FGFR2 mutant-driven endometrial cancers. Thus, we evaluated the activity of AZD4547 against four different endometrial cancer cells, including AN3-CA, MFE296, MFE280, and HEC1A, where all but HEC1A cells express distinctive FGFR2 mutations. We found that AZD4547 exhibits potent antiproliferative activity (EC50 = 31 nmol/L) against AN3-CA cells harboring FGFR2-K310R/N550K mutant. Analysis using a phospho-kinase array revealed that AZD4547 blocks FGFR2 downstream signaling, such as p38, ERK1/2, JNK, p70S6K, and PLCγ. Moreover, oral administration of AZD4547 (30 mg/kg, every day) remarkably delayed tumor growth in a mouse xenograft model of AN3-CA cells. Unbiased reporter gene assay showed that AZD4547 antagonizes the aFGF-induced activation of several transcription factors, including EGR1, ELK-1/SRF, AP-1, and NFκB. Genome-wide transcriptome analysis revealed that AZD4547 perturbs a number of transcriptions, and EGR1 was identified as one of the major targets of AZD4547. The significance of the FGFR2-EGR1 axis in endometrial cancer progression has not been reported. In addition, using kinome-wide inhibition profiling analysis, we first identified potential new target kinases of AZD4547, including MAP4K3, MAP4K5, IRR, RET, and FLT3. Our study demonstrated that AZD4547 exhibits its therapeutic activity against endometrial cancer cells by perturbing various regulatory mechanisms related to FGFR signaling.

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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 wild-type endometrial cancer resistant AZD4547 Preclinical - Cell culture Actionable In a preclinical study, endometrial cells with Fgfr2 wild-type were resistant to the anti-proliferative effects of AZD4547 (PMID: 26294741). 26294741
FGFR2 K310R FGFR2 N550K endometrial cancer sensitive AZD4547 Preclinical - Pdx & cell culture Actionable In a preclinical study, AZD4547 inhibited proliferation of endometrial cells and delayed tumor growth in cell-line derived xenografts harboring the Fgfr2 double mutant, K310R, N550K (PMID: 26294741). 26294741
FGFR2 N550K endometrial cancer predicted - sensitive AZD4547 Preclinical - Cell culture Actionable In a preclinical study, endometrial cells harboring Fgfr2 N550K were less sensitive to the anti-proliferative effects of AZD4547 than the Fgfr2 double mutant, K310R, N550K (PMID: 26294741). 26294741
FGFR2 S252W endometrial cancer decreased response AZD4547 Preclinical - Cell culture Actionable In a preclinical study, endometrial cells harboring Fgfr2 S252W were less sensitive to the anti-proliferative effects of AZD4547 than the Fgfr2 double mutant, K310R, N550K (PMID: 26294741). 26294741
FGFR2 over exp endometrial cancer resistant AZD4547 Preclinical - Cell culture Actionable In a preclinical study, endometrial cells with Fgfr2 overexpression were resistant to the anti-proliferative effects of AZD4547 (PMID: 26294741). 26294741