3-(2-6-dichloro-3-5-dimethoxyphenyl)-1-(6-(4-(4-ethylpiperazin-1-yl)-phenylamino)pyrimidin-4-yl)-1-methylurea and Colorectal-Neoplasms

3-(2-6-dichloro-3-5-dimethoxyphenyl)-1-(6-(4-(4-ethylpiperazin-1-yl)-phenylamino)pyrimidin-4-yl)-1-methylurea has been researched along with Colorectal-Neoplasms* in 5 studies

Other Studies

5 other study(ies) available for 3-(2-6-dichloro-3-5-dimethoxyphenyl)-1-(6-(4-(4-ethylpiperazin-1-yl)-phenylamino)pyrimidin-4-yl)-1-methylurea and Colorectal-Neoplasms

ArticleYear
Significance of FGF9 gene in resistance to anti-EGFR therapies targeting colorectal cancer: A subset of colorectal cancer patients with FGF9 upregulation may be resistant to anti-EGFR therapies.
    Molecular carcinogenesis, 2017, Volume: 56, Issue:1

    Although fibroblast growth factor (FGF) signals are strongly associated with malignancy, limited information is available regarding the role of the FGF9 signal in colorectal cancer (CRC). In this study, we investigated the frequency of FGF9 amplification in CRC clinical specimens and the association between the FGF9 gene and resistance to anti-EGFR therapies. In clinical samples, an FGF9 copy number gain of >5 copies was observed at a frequency of 8/145 (5.5%) and tended to be related to wild-type KRAS (7/96, 7.3%). Furthermore, FGF9 amplification was not observed in any of the samples from the 15 responders to anti-EGFR therapies but was observed in one sample from the seven non-responders with wild-type KRAS, and two samples from non-responders also had high FGF9 mRNA expression levels. FGF9 amplification was validated using a fluorescence in situ hybridization (FISH) analysis, and FGF9-amplified sections showed readily detectable signals originating from FGF9 protein when examined using immunohistochemistry. In both the in vitro and in vivo experiments using FGF9-overexpressing CRC cell lines, FGF9 overexpression induced strong resistance to anti-EGFR therapies via the enforced FGFR signal, and this resistance was cancelled by the application of an FGFR inhibitor. Considering these results, the FGF9 gene may play an important role in resistance to anti-EGFR therapies in patients with CRC, and such resistance might be overcome by combined treatment with an anti-FGFR inhibitor. These findings strongly encourage the development of FGFR-targeted therapy for CRC patients with FGF9 gene upregulation. © 2016 Wiley Periodicals, Inc.

    Topics: Aged; Animals; Antineoplastic Agents; Colon; Colorectal Neoplasms; Drug Resistance, Neoplasm; ErbB Receptors; Female; Fibroblast Growth Factor 9; Humans; Male; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Phenylurea Compounds; Pyrimidines; Receptors, Fibroblast Growth Factor; Rectum; Up-Regulation

2017
Avatars Identify Genetic Sources of Drug Response.
    Cancer discovery, 2016, Volume: 6, Issue:1

    Using mouse avatars implanted with liver metastases of late-stage colorectal cancers, researchers uncovered mutations in five genes-ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1-that seem to promote cetuximab resistance. They also found that mutations in IRS2 may boost tumors' vulnerability to anti-EGFR therapy and tested specific therapies in the mice to gauge the drugs' effectiveness.

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Drug Resistance, Neoplasm; Exome; Mice; Mutation; Phenylurea Compounds; Precision Medicine; Pyrimidines; Sequence Analysis, DNA; Xenograft Model Antitumor Assays

2016
Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma.
    Hepatology (Baltimore, Md.), 2014, Volume: 59, Issue:4

    Cholangiocarcinoma is an intractable cancer, with limited therapeutic options, in which the molecular mechanisms underlying tumor development remain poorly understood. Identification of a novel driver oncogene and applying it to targeted therapies for molecularly defined cancers might lead to improvements in the outcome of patients. We performed massively parallel whole transcriptome sequencing in eight specimens from cholangiocarcinoma patients without KRAS/BRAF/ROS1 alterations and identified two fusion kinase genes, FGFR2-AHCYL1 and FGFR2-BICC1. In reverse-transcriptase polymerase chain reaction (RT-PCR) screening, the FGFR2 fusion was detected in nine patients with cholangiocarcinoma (9/102), exclusively in the intrahepatic subtype (9/66, 13.6%), rarely in colorectal (1/149) and hepatocellular carcinoma (1/96), and none in gastric cancer (0/212). The rearrangements were mutually exclusive with KRAS/BRAF mutations. Expression of the fusion kinases in NIH3T3 cells activated MAPK and conferred anchorage-independent growth and in vivo tumorigenesis of subcutaneous transplanted cells in immune-compromised mice. This transforming ability was attributable to its kinase activity. Treatment with the fibroblast growth factor receptor (FGFR) kinase inhibitors BGJ398 and PD173074 effectively suppressed transformation.. FGFR2 fusions occur in 13.6% of intrahepatic cholangiocarcinoma. The expression pattern of these fusions in association with sensitivity to FGFR inhibitors warrant a new molecular classification of cholangiocarcinoma and suggest a new therapeutic approach to the disease.

    Topics: Adenosylhomocysteinase; Aged; Animals; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinoma, Hepatocellular; Cholangiocarcinoma; Colorectal Neoplasms; Female; Humans; In Vitro Techniques; Liver Neoplasms; Male; Mice; Mice, Nude; Middle Aged; Molecular Sequence Data; NIH 3T3 Cells; Phenylurea Compounds; Pyrimidines; Receptor, Fibroblast Growth Factor, Type 2; Receptors, Fibroblast Growth Factor; RNA-Binding Proteins; Stomach Neoplasms; Transcriptome

2014
Fibroblast growth factor receptor 4 (FGFR4): a targetable regulator of drug resistance in colorectal cancer.
    Cell death & disease, 2014, Feb-06, Volume: 5

    The discovery of underlying mechanisms of drug resistance, and the development of novel agents to target these pathways, is a priority for patients with advanced colorectal cancer (CRC). We previously undertook a systems biology approach to design a functional genomic screen and identified fibroblast growth factor receptor 4 (FGFR4) as a potential mediator of drug resistance. The aim of this study was to examine the role of FGFR4 in drug resistance using RNAi and the small-molecule inhibitor BGJ398 (Novartis). We found that FGFR4 is highly expressed at the RNA and protein levels in colon cancer tumour tissue compared with normal colonic mucosa and other tumours. Silencing of FGFR4 reduced cell viability in a panel of colon cancer cell lines and increased caspase-dependent apoptosis. A synergistic interaction was also observed between FGFR4 silencing and 5-fluorouracil (5-FU) and oxaliplatin chemotherapy in colon cancer cell lines. Mechanistically, FGFR4 silencing decreased activity of the pro-survival STAT3 transcription factor and expression of the anti-apoptotic protein c-FLIP. Furthermore, silencing of STAT3 resulted in downregulation of c-FLIP protein expression, suggesting that FGFR4 may regulate c-FLIP expression via STAT3. A similar phenotype and downstream pathway changes were observed following FGFR4 silencing in cell lines resistant to 5-FU, oxaliplatin and SN38 and upon exposure of parental cells to the FGFR small-molecule inhibitor BGJ398. Our results indicate that FGFR4 is a targetable regulator of chemo-resistance in CRC, and hence inhibiting FGFR4 in combination with 5-FU and oxaliplatin is a potential therapeutic strategy for this disease.

    Topics: Antineoplastic Agents; Apoptosis; Caspases; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Drug Resistance, Neoplasm; Fluorouracil; Humans; Phenylurea Compounds; Pyrimidines; Receptor, Fibroblast Growth Factor, Type 4; STAT3 Transcription Factor

2014
Fibroblast growth factor receptor 1 as a putative therapy target in colorectal cancer.
    Digestion, 2013, Volume: 88, Issue:3

    Resembling a potential therapeutic drug target, fibroblast growth factor receptor 1 (FGFR1) amplification and expression was assessed in 515 human colorectal cancer (CRC) tissue samples, lymph node metastases and CRC cell lines.. FGFR1 amplification status was determined using fluorescence in situ hybridization. Additionally, we assessed protein levels employing Western blots and immunohistochemistry. The FGFR1 mRNA localization was analyzed using mRNA in situ hybridization. Functional studies employed the FGFR inhibitor NVP-BGJ398.. Of 454 primary CRCs, 24 displayed FGFR1 amplification. 92/94 lymph node metastases presented the same amplification status as the primary tumor. Of 99 investigated tumors, 18 revealed membranous activated pFGFR1 protein. FGFR1 mRNA levels were independent of the amplification status or pFGFR1 protein occurrence. In vitro, a strong antiproliferative effect of NVP-BGJ398 could be detected in cell lines exhibiting high FGFR1 protein.. FGFR1 is a potential therapeutic target in a subset of CRC. FGFR1 protein is likely to represent a central factor limiting the efficacy of FGFR inhibitors. The lack of correlation between its evaluation at genetic/mRNA level and its protein occurrence indicates that the assessment of the receptor at an immunohistochemical level most likely represents a suitable way to assess FGFR1 as a predictive biomarker for patient selection in future clinical trials.

    Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Drug Screening Assays, Antitumor; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Phenylurea Compounds; Pyrimidines; Receptor, Fibroblast Growth Factor, Type 1; RNA, Messenger

2013