Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma.

Abstract

Cholangiocarcinoma, also known as bile duct cancer, is the second most common primary hepatic carcinoma with a median survival of less than 2 years. The molecular mechanisms underlying the development of this disease are not clear. To survey activated tyrosine kinases signaling in cholangiocarcinoma, we employed immunoaffinity profiling coupled to mass spectrometry and identified DDR1, EPHA2, EGFR, and ROS tyrosine kinases, along with over 1,000 tyrosine phosphorylation sites from about 750 different proteins in primary cholangiocarcinoma patients. Furthermore, we confirmed the presence of ROS kinase fusions in 8.7% (2 out of 23) of cholangiocarcinoma patients. Expression of the ROS fusions in 3T3 cells confers transforming ability both in vitro and in vivo, and is responsive to its kinase inhibitor. Our data demonstrate that ROS kinase is a promising candidate for a therapeutic target and for a diagnostic molecular marker in cholangiocarcinoma. The identification of ROS tyrosine kinase fusions in cholangiocarcinoma, along with the presence of other ROS kinase fusions in lung cancer and glioblastoma, suggests that a more broadly based screen for activated ROS kinase in cancer is warranted.

• Authors: Ting-Lei Gu, Xiaxing Deng, Feizhou Huang, Meghan Tucker, Katherine Crosby, Victoria Rimkunas, Yi Wang, Gang Deng, Lei Zhu, Zhiping Tan, Yerong Hu, Chunlin Wu, Julie Nardone, Joan MacNeill, Jianmin Ren, Cynthia Reeves, Gregory Innocenti, Brett Norris, Jin Yuan, Jian Yu, Herbert Haack, Baiyong Shen, Chenghong Peng, Hongwei Li, Xinmin Zhou, Xunyang Liu, John Rush, Michael J Comb
• Journal: PloS one (PLoS One) Vol. 6 Issue 1 Pg. e15640 (Jan 06 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21253578 (Publication Type: Journal Article)

Chemical References

• Oncogene Proteins, Fusion
• Proto-Oncogene Proteins
• Protein-Tyrosine Kinases
• ROS1 protein, human

Topics

• Animals
• Bile Duct Neoplasms (enzymology)
• Bile Ducts, Intrahepatic
• Cell Line, Tumor
• Cholangiocarcinoma (enzymology)
• Humans
• Immunoassay
• Mice
• Mice, Nude
• Oncogene Proteins, Fusion (genetics, metabolism)
• Phosphorylation
• Protein-Tyrosine Kinases (analysis, genetics, metabolism)
• Proto-Oncogene Proteins (genetics, metabolism)
• Signal Transduction