Signaling networks assembled by oncogenic EGFR and c-Met.
A major question regarding the sensitivity of solid tumors to targeted kinase inhibitors is why some tumors respond and others do not. The observation that many tumors express EGF receptor (EGFR), yet only a small subset with EGFR-activating mutations respond clinically to EGFR inhibitors (EGFRIs), suggests that responsive tumors uniquely depend on EGFR signaling for their survival. The nature of this dependence is not understood. Here, we investigate dependence on EGFR signaling by comparing non-small-cell lung cancer cell lines driven by EGFR-activating mutations and genomic amplifications using a global proteomic analysis of phospho-tyrosine signaling. We identify an extensive receptor tyrosine kinase signaling network established in cells expressing mutated and activated EGFR or expressing amplified c-Met. We show that in drug sensitive cells the targeted tyrosine kinase drives other RTKs and an extensive network of downstream signaling that collapse with drug treatment. Comparison of the signaling networks in EGFR and c-Met-dependent cells identify a "core network" of approximately 50 proteins that participate in pathways mediating drug response.
Guo
Ailan
A
Cell Signaling Technology Inc., 3 Trask Lane, Danvers, MA 01923, USA.
Villén
Judit
J
Kornhauser
Jon
J
Lee
Kimberly A
KA
Stokes
Matthew P
MP
Rikova
Klarisa
K
Possemato
Anthony
A
Nardone
Julie
J
Innocenti
Gregory
G
Wetzel
Randall
R
Wang
Yi
Y
MacNeill
Joan
J
Mitchell
Jeffrey
J
Gygi
Steven P
SP
Rush
John
J
Polakiewicz
Roberto D
RD
Comb
Michael J
MJ
D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism*; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D008954:Models, Biological; D009362:Neoplasm Metastasis; D019000:Phosphotyrosine / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction
D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D019000:Phosphotyrosine; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met; D000077156:Gefitinib