Only a subset of Met-activated pathways are required to sustain oncogene addiction.

Andrea Bertotti, Mike F. Burbridge, Stefania Gastaldi, Francesco Galimi, Davide Torti, Enzo Medico, Silvia Giordano, Simona Corso, Gaëlle Rolland-Valognes, Brian P. Lockhart, John A. Hickman, Paolo M. Comoglio, Livio Trusolino

Research output: Contribution to journalArticlepeer-review


Tumor onset and progression require the accumulation of many genetic and epigenetic lesions. In some cases, however, cancer cells rely on only one of these lesions to maintain their malignant properties, and this dependence results in tumor regression upon oncogene inactivation ("oncogene addiction"). Determining which nodes of the many networks operative in the transformed phenotype specifically mediate this response to oncogene neutralization is crucial to identifying the vulnerabilities of cancer. Using the Met receptor as the major model system, we combined multiplex phosphoproteomics, genome-wide expression profiling, and functional assays in various cancer cells addicted to oncogenic receptor tyrosine kinases. We found that Met blockade affected a limited subset of Met downstream signals: Little or no effect was observed for several pathways downstream of Met; instead, only a restricted and pathway-specific signature of transducers and transcriptional effectors downstream of Ras or phosphoinositide 3-kinase (PI3K) was inactivated. An analogous signature was also generated by inhibition of epidermal growth factor receptor in a different cellular context, suggesting a stereotyped response that likely is independent of receptor type or tissue origin. Biologically, Met inhibition led to cell-cycle arrest. Inhibition of Ras-dependent signals and PI3K-dependent signals also resulted in cell-cycle arrest, whereas cells in which Met was inhibited proliferated when Ras or PI3K signaling was active. These findings uncover "dominant" and "recessive" nodes among the numerous oncogenic networks regulated by receptor tyrosine kinases and active in cancer, with the Ras and PI3K pathways as determinants of therapeutic response.

Original languageEnglish
JournalScience Signaling
Issue number102
Publication statusPublished - 2009

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology


Dive into the research topics of 'Only a subset of Met-activated pathways are required to sustain oncogene addiction.'. Together they form a unique fingerprint.

Cite this