In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 1269-1269
Abstract:
Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States. A number of genes that have somatic mutations including CDKN2A, SMAD4, TP53 and KRAS have been linked to pancreatic cancer. Recently, a comprehensive genomic analysis was performed in a panel of 14 primary pancreatic cancer cell lines and 10 xenografts, in which ∼1,500 somatic alterations were identified and a core set of 12 activated signaling pathways were defined. We decided to use a phosphoproteomics approach to identify tyrosine kinase signaling pathways that could serve as attractive therapeutic targets. Based on immunoblotting with anti-phosphotyrosine antibodies, we observed a heterogeneous pattern of tyrosine phosphorylation in the 14 primary pancreatic cancer cell lines whose genomes have been sequenced previously, which indicated that different tyrosine kinases were likely activated in different cells. To identify these kinases, phosphotyrosine-containing peptides were enriched by immunoprecipitation by anti-phosphotyrosine antibodies and analyzed on a high resolution Fourier transform mass spectrometer coupled to nanoflow reversed phase liquid chromatography. W employed the SILAC methodology to quantitate tyrosine phosphorylated peptides across the panel of cell lines. Our preliminary data indicates that the approach used in this study is suitable for global profiling of tyrosine kinase pathways that are abnormally activated in cancers. The differential alteration of tyrosine kinases was confirmed from the accurate quantitative tyrosine phosphoproteomic analysis. For example, HPNE, a normal pancreatic cell line showed the lowest level of phosphotyrosine levels, while each pancreatic cancer cell line could be differentiated based on its own set of activated tyrosine kinases. Interestingly, some of tyrosine kinases were activated in a small number of cell lines (e.g. AXL, SYK, DDR2, RON and RET), while other tyrosine kinases were found to be activated more broadly (e.g. YES1, TYK2, EPHA2 and EPHB4). Overall, we conclude that these aberrantly activated tyrosine kinases could be targeted to develop newer therapeutic regimens. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL . Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1269. doi:1538-7445.AM2012-1269
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2012-1269
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2012
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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