title: Only a subset of Met-activated pathways are required to sustain oncogene addiction.
abstract: 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.
authors.affiliation: Division of Molecular Oncology, Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, 10060 Candiolo (Torino), Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bertotti
authors.forename: Mike F
authors.initials: MF
authors.lastname: Burbridge
authors.forename: Stefania
authors.initials: S
authors.lastname: Gastaldi
authors.forename: Francesco
authors.initials: F
authors.lastname: Galimi
authors.forename: Davide
authors.initials: D
authors.lastname: Torti
authors.forename: Enzo
authors.initials: E
authors.lastname: Medico
authors.forename: Silvia
authors.initials: S
authors.lastname: Giordano
authors.forename: Simona
authors.initials: S
authors.lastname: Corso
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Rolland-Valognes
authors.forename: Brian P
authors.initials: BP
authors.lastname: Lockhart
authors.forename: John A
authors.initials: JA
authors.lastname: Hickman
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Comoglio
authors.forename: Livio
authors.initials: L
authors.lastname: Trusolino
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D066246:ErbB Receptors / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D009857:Oncogenes; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D015689:Oncogene Protein p21(ras)