title: Antitumor Effects and Mechanisms of AZD4547 on FGFR2-Deregulated Endometrial Cancer Cells.
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.
authors: KU-KIST Graduate School of Converging Science and Technology, Korea University, Seongbuk-gu, Seoul, Republic of Korea.
authors: Yeonui
authors: Y
authors: Kwak
authors: KU-KIST Graduate School of Converging Science and Technology, Korea University, Seongbuk-gu, Seoul, Republic of Korea.
authors: Hanna
authors: H
authors: Cho
authors: Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seongbuk-gu, Seoul, Republic of Korea.
authors: Wooyoung
authors: W
authors: Hur
authors: KU-KIST Graduate School of Converging Science and Technology, Korea University, Seongbuk-gu, Seoul, Republic of Korea. Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seongbuk-gu, Seoul, Republic of Korea. tbsim@kist.re.kr tbsim@korea.ac.kr.
authors: Taebo
authors: T
authors: Sim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020125:Mutation, Missense; D010879:Piperazines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics* / Q000378:metabolism; D018808:Transcription Factor AP-1; D059467:Transcriptome / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C572463:AZD4547; D000970:Antineoplastic Agents; D001549:Benzamides; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D010879:Piperazines; D011720:Pyrazoles; D018808:Transcription Factor AP-1; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2