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Antitumor Effects and Mechanisms of AZD4547 on FGFR2-Deregulated Endometrial Cancer Cells
- Source :
- Molecular Cancer Therapeutics. 14:2292-2302
- Publication Year :
- 2015
- Publisher :
- American Association for Cancer Research (AACR), 2015.
-
Abstract
- 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. Mol Cancer Ther; 14(10); 2292–302. ©2015 AACR.
- Subjects :
- Cancer Research
medicine.medical_specialty
Cell cycle checkpoint
MAP Kinase Signaling System
Mutation, Missense
Mice, Nude
Antineoplastic Agents
Apoptosis
Biology
Piperazines
Transcriptome
Inhibitory Concentration 50
Cell Line, Tumor
Internal medicine
medicine
Animals
Humans
Receptor, Fibroblast Growth Factor, Type 2
Cell Proliferation
Early Growth Response Protein 1
Regulation of gene expression
Mice, Inbred BALB C
Reporter gene
Kinase
Cell growth
Endometrial cancer
Cell Cycle Checkpoints
medicine.disease
Xenograft Model Antitumor Assays
Endometrial Neoplasms
Gene Expression Regulation, Neoplastic
Transcription Factor AP-1
Endocrinology
Oncology
Cell culture
Benzamides
Cancer research
Pyrazoles
Female
Subjects
Details
- ISSN :
- 15388514 and 15357163
- Volume :
- 14
- Database :
- OpenAIRE
- Journal :
- Molecular Cancer Therapeutics
- Accession number :
- edsair.doi.dedup.....a09ff3559685e4282be0f21931b32fd7