Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	14	10	2015 Oct	2292-302	Mol Cancer Ther

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 N550K	endometrial cancer	predicted - sensitive	Fexagratinib	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 K310R FGFR2 N550K	endometrial cancer	sensitive	Fexagratinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, AZD4547 inhibited proliferation of endometrial cancer cells harboring an FGFR2 K310R/N550K double mutation in culture and delayed tumor growth in xenograft models (PMID: 26294741).	26294741
FGFR2 wild-type	endometrial cancer	resistant	Fexagratinib	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 over exp	endometrial cancer	resistant	Fexagratinib	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
FGFR2 S252W	endometrial cancer	decreased response	Fexagratinib	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