Dynamic reprogramming of signaling upon met inhibition reveals a mechanism of drug resistance in gastric cancer.
The Met receptor tyrosine kinase is activated or genetically amplified in some gastric cancers, but resistance to small-molecule inhibitors of Met often emerges in patients. We found that Met abundance correlated with a proliferation marker in patient gastric tumor sections, and gastric cancer cell lines that have MET amplifications depended on Met for proliferation and anchorage-independent growth in culture. Inhibition of Met induced temporal changes in gene expression in the cell lines, initiated by a rapid decrease in the expression of genes encoding transcription factors, followed by those encoding proteins involved in epithelial-mesenchymal transition, and finally those encoding cell cycle-related proteins. In the gastric cancer cell lines, microarray and chromatin immunoprecipitation analysis revealed considerable overlap between genes regulated in response to Met stimulation and those regulated by signal transducer and activator of transcription 3 (STAT3). The activity of STAT3, extracellular signal-regulated kinase (ERK), and the kinase Akt was decreased by Met inhibition, but only inhibitors of STAT3 were as effective as the Met inhibitor in decreasing tumor cell proliferation in culture and in xenografts, suggesting that STAT3 mediates the pro-proliferative program induced by Met. However, the phosphorylation of ERK increased after prolonged Met inhibition in culture, correlating with decreased abundance of the phosphatases DUSP4 and DUSP6, which inhibit ERK. Combined inhibition of Met and the mitogen-activated protein kinase kinase (MEK)-ERK pathway induced greater cell death in cultured gastric cancer cells than did either inhibitor alone. These findings indicate combination therapies that may counteract resistance to Met inhibitors.
1Department of Biochemistry, McGill University, Montréal, Québec H3A 0G4, Canada.
Andrea Z
AZ
Lai
Sean
S
Cory
Hong
H
Zhao
Mathieu
M
Gigoux
Anie
A
Monast
Marie-Christine
MC
Guiot
Sidong
S
Huang
Ali
A
Tofigh
Crista
C
Thompson
Monica
M
Naujokas
Victoria A
VA
Marcus
Nicholas
N
Bertos
Bita
B
Sehat
Rushika M
RM
Perera
Emily S
ES
Bell
Brent D G
BD
Page
Patrick T
PT
Gunning
Lorenzo E
LE
Ferri
Michael
M
Hallett
Morag
M
Park
D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics / Q000378:metabolism; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D054639:Mitogen-Activated Protein Kinase Phosphatases; C490583:DUSP4 protein, human; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6; D054637:Dual-Specificity Phosphatases