Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma.
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.
Cell Signaling Technology, Danvers, Massachusetts, United States of America. tgu@cellsignal.com
Ting-Lei
TL
Gu
Xiaxing
X
Deng
Feizhou
F
Huang
Meghan
M
Tucker
Katherine
K
Crosby
Victoria
V
Rimkunas
Yi
Y
Wang
Gang
G
Deng
Lei
L
Zhu
Zhiping
Z
Tan
Yerong
Y
Hu
Chunlin
C
Wu
Julie
J
Nardone
Joan
J
MacNeill
Jianmin
J
Ren
Cynthia
C
Reeves
Gregory
G
Innocenti
Brett
B
Norris
Jin
J
Yuan
Jian
J
Yu
Herbert
H
Haack
Baiyong
B
Shen
Chenghong
C
Peng
Hongwei
H
Li
Xinmin
X
Zhou
Xunyang
X
Liu
John
J
Rush
Michael J
MJ
Comb
D000818:Animals; D001650:Bile Duct Neoplasms / Q000201:enzymology*; D001653:Bile Ducts, Intrahepatic; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000201:enzymology*; D006801:Humans; D007118:Immunoassay; D051379:Mice; D008819:Mice, Nude; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human
Oncologist. 2005 Apr;10(4):269-81
15821247
Cancer Res. 2006 Aug 1;66(15):7473-81
16885344
Nature. 2006 Jan 19;439(7074):353-7
16273092
Biochim Biophys Acta. 2009 Jan;1795(1):37-52
18778756
Nature. 2001 May 17;411(6835):355-65
11357143
J Hepatol. 2008 Feb;48(2):237-45
18068850
Blood. 2007 Jul 1;110(1):323-33
17360941
J Biol Chem. 2001 Aug 3;276(31):29456-65
11384996
Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):270-5
17185414
Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4477-82
15070743
Science. 2002 Dec 6;298(5600):1912-34
12471243
Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13790-5
11707567
Nat Rev Cancer. 2004 Mar;4(3):177-83
14993899
Cell. 2007 Dec 14;131(6):1190-203
18083107
Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):916-21
12538861
Cancer Res. 2009 Mar 15;69(6):2180-4
19276365
Nat Rev Cancer. 2006 Sep;6(9):674-87
16929323
Pathol Int. 2008 Apr;58(4):226-32
18324915
Nat Biotechnol. 2005 Jan;23(1):94-101
15592455
Proteomics. 2010 Mar;10(6):1150-9
20101611
Genes Chromosomes Cancer. 2003 May;37(1):58-71
12661006
N Engl J Med. 1999 Oct 28;341(18):1368-78
10536130
Hepatology. 2008 Jul;48(1):308-21
18536057