Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.
Despite the success of tyrosine kinase-based cancer therapeutics, for most solid tumors the tyrosine kinases that drive disease remain unknown, limiting our ability to identify drug targets and predict response. Here we present the first large-scale survey of tyrosine kinase activity in lung cancer. Using a phosphoproteomic approach, we characterize tyrosine kinase signaling across 41 non-small cell lung cancer (NSCLC) cell lines and over 150 NSCLC tumors. Profiles of phosphotyrosine signaling are generated and analyzed to identify known oncogenic kinases such as EGFR and c-Met as well as novel ALK and ROS fusion proteins. Other activated tyrosine kinases such as PDGFRalpha and DDR1 not previously implicated in the genesis of NSCLC are also identified. By focusing on activated cell circuitry, the approach outlined here provides insight into cancer biology not available at the chromosomal and transcriptional levels and can be applied broadly across all human cancers.
Rikova
Klarisa
K
Cell Signaling Technology, 3 Trask Lane, Danvers, MA 01923, USA.
Guo
Ailan
A
Zeng
Qingfu
Q
Possemato
Anthony
A
Yu
Jian
J
Haack
Herbert
H
Nardone
Julie
J
Lee
Kimberly
K
Reeves
Cynthia
C
Li
Yu
Y
Hu
Yerong
Y
Tan
Zhiping
Z
Stokes
Matthew
M
Sullivan
Laura
L
Mitchell
Jeffrey
J
Wetzel
Randy
R
Macneill
Joan
J
Ren
Jian Min
JM
Yuan
Jin
J
Bakalarski
Corey E
CE
Villen
Judit
J
Kornhauser
Jon M
JM
Smith
Bradley
B
Li
Daiqiang
D
Zhou
Xinmin
X
Gygi
Steven P
SP
Gu
Ting-Lei
TL
Polakiewicz
Roberto D
RD
Rush
John
J
Comb
Michael J
MJ
D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D050939:Gene Fusion; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*
D019000:Phosphotyrosine; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha