Dynamic Reprogramming of Signaling Upon Met Inhibition Reveals a Mechanism of Drug Resistance in Gastric Cancer

Sci. Signal., 22 April 2014
Vol. 7, Issue 322, p. ra38
DOI: 10.1126/scisignal.2004839

Dynamic Reprogramming of Signaling Upon Met Inhibition Reveals a Mechanism of Drug Resistance in Gastric Cancer

  1. Andrea Z. Lai1,2,
  2. Sean Cory2,3,
  3. Hong Zhao2,4,
  4. Mathieu Gigoux2,
  5. Anie Monast2,
  6. Marie-Christine Guiot5,6,
  7. Sidong Huang1,2,
  8. Ali Tofigh2,3,
  9. Crista Thompson2,
  10. Monica Naujokas2,
  11. Victoria A. Marcus5,
  12. Nicholas Bertos2,4,
  13. Bita Sehat2,
  14. Rushika M. Perera2,7,
  15. Emily S. Bell1,2,
  16. Brent D. G. Page8,
  17. Patrick T. Gunning8,
  18. Lorenzo E. Ferri7,
  19. Michael Hallett2,3, and
  20. Morag Park1,2,5,9,*
  1. 1Department of Biochemistry, McGill University, Montréal, Québec H3A 0G4, Canada.
  2. 2Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 0G4, Canada.
  3. 3McGill Centre for Bioinformatics, Montréal, Québec H3A 0G4, Canada.
  4. 4Breast Cancer Functional Genomics Group, McGill University, Montréal, Québec H3A 0G4, Canada.
  5. 5Department of Pathology, McGill University, Montréal, Québec H3A 0G4, Canada.
  6. 6Montréal Neurological Institute, McGill University, Montréal, Québec H3A 2B4, Canada.
  7. 7Department of Surgery, McGill University, Montréal, Québec H3A 0G4, Canada.
  8. 8Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario L5L 1C6, Canada.
  9. 9Department of Oncology, McGill University, Montréal, Québec H3A 0G4, Canada.
  1. *Corresponding author. E-mail: morag.park{at}mcgill.ca

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.

Citation:

A. Z. Lai, S. Cory, H. Zhao, M. Gigoux, A. Monast, M.-C. Guiot, S. Huang, A. Tofigh, C. Thompson, M. Naujokas, V. A. Marcus, N. Bertos, B. Sehat, R. M. Perera, E. S. Bell, B. D. Page, P. T. Gunning, L. E. Ferri, M. Hallett, and M. Park, Dynamic Reprogramming of Signaling Upon Met Inhibition Reveals a Mechanism of Drug Resistance in Gastric Cancer. Sci. Signal. 7, ra38 (2014).
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