Dynamic reprogramming of signaling upon met inhibition reveals a mechanism of drug resistance in gastric cancer

Andrea Z. Lai, Sean Cory, Hong Zhao, Mathieu Gigoux, Anie Monast, Marie Christine Guiot, Sidong Huang, Ali Tofigh, Crista Thompson, Monica Naujokas, Victoria A. Marcus, Nicholas Bertos, Bita Sehat, Rushika M. Perera, Emily Bell, Brent D.G. Page, Patrick T. Gunning, Lorenzo E. Ferri, Michael Hallett, Morag Park

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Article numberra38
JournalScience Signaling
Volume7
Issue number322
DOIs
StatePublished - Apr 22 2014

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STAT3 Transcription Factor
Extracellular Signal-Regulated MAP Kinases
Drug Resistance
Stomach Neoplasms
Cells
Mitogen-Activated Protein Kinase Kinases
Cell Line
Pharmaceutical Preparations
Tumors
Gene Expression
Cell Cycle Proteins
Epithelial-Mesenchymal Transition
Chromatin Immunoprecipitation
Receptor Protein-Tyrosine Kinases
Phosphoric Monoester Hydrolases
Phosphorylation
Heterografts
Gene encoding
Cell proliferation
Cell death

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Lai, Andrea Z. ; Cory, Sean ; Zhao, Hong ; Gigoux, Mathieu ; Monast, Anie ; Guiot, Marie Christine ; Huang, Sidong ; Tofigh, Ali ; Thompson, Crista ; Naujokas, Monica ; Marcus, Victoria A. ; Bertos, Nicholas ; Sehat, Bita ; Perera, Rushika M. ; Bell, Emily ; Page, Brent D.G. ; Gunning, Patrick T. ; Ferri, Lorenzo E. ; Hallett, Michael ; Park, Morag. / Dynamic reprogramming of signaling upon met inhibition reveals a mechanism of drug resistance in gastric cancer. In: Science Signaling. 2014 ; Vol. 7, No. 322.
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abstract = "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.",
author = "Lai, {Andrea Z.} and Sean Cory and Hong Zhao and Mathieu Gigoux and Anie Monast and Guiot, {Marie Christine} and Sidong Huang and Ali Tofigh and Crista Thompson and Monica Naujokas and Marcus, {Victoria A.} and Nicholas Bertos and Bita Sehat and Perera, {Rushika M.} and Emily Bell and Page, {Brent D.G.} and Gunning, {Patrick T.} and Ferri, {Lorenzo E.} and Michael Hallett and Morag Park",
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Lai, AZ, Cory, S, Zhao, H, Gigoux, M, Monast, A, Guiot, MC, Huang, S, Tofigh, A, Thompson, C, Naujokas, M, Marcus, VA, Bertos, N, Sehat, B, Perera, RM, Bell, E, Page, BDG, Gunning, PT, Ferri, LE, Hallett, M & Park, M 2014, 'Dynamic reprogramming of signaling upon met inhibition reveals a mechanism of drug resistance in gastric cancer', Science Signaling, vol. 7, no. 322, ra38. https://doi.org/10.1126/scisignal.2004839

Dynamic reprogramming of signaling upon met inhibition reveals a mechanism of drug resistance in gastric cancer. / Lai, Andrea Z.; Cory, Sean; Zhao, Hong; Gigoux, Mathieu; Monast, Anie; Guiot, Marie Christine; Huang, Sidong; Tofigh, Ali; Thompson, Crista; Naujokas, Monica; Marcus, Victoria A.; Bertos, Nicholas; Sehat, Bita; Perera, Rushika M.; Bell, Emily; Page, Brent D.G.; Gunning, Patrick T.; Ferri, Lorenzo E.; Hallett, Michael; Park, Morag.

In: Science Signaling, Vol. 7, No. 322, ra38, 22.04.2014.

Research output: Contribution to journalArticle

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T1 - Dynamic reprogramming of signaling upon met inhibition reveals a mechanism of drug resistance in gastric cancer

AU - Lai, Andrea Z.

AU - Cory, Sean

AU - Zhao, Hong

AU - Gigoux, Mathieu

AU - Monast, Anie

AU - Guiot, Marie Christine

AU - Huang, Sidong

AU - Tofigh, Ali

AU - Thompson, Crista

AU - Naujokas, Monica

AU - Marcus, Victoria A.

AU - Bertos, Nicholas

AU - Sehat, Bita

AU - Perera, Rushika M.

AU - Bell, Emily

AU - Page, Brent D.G.

AU - Gunning, Patrick T.

AU - Ferri, Lorenzo E.

AU - Hallett, Michael

AU - Park, Morag

PY - 2014/4/22

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N2 - 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.

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