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Sci. Signal., 8 December 2009
Vol. 2, Issue 100, p. ra80
[DOI: 10.1126/scisignal.2000643]


Only a Subset of Met-Activated Pathways Are Required to Sustain Oncogene Addiction

Andrea Bertotti1, Mike F. Burbridge2*, Stefania Gastaldi1*, Francesco Galimi1*, Davide Torti1*, Enzo Medico3, Silvia Giordano1, Simona Corso1, Gaëlle Rolland-Valognes4, Brian P. Lockhart4, John A. Hickman2, Paolo M. Comoglio1{dagger}, and Livio Trusolino1{dagger}

1 Division of Molecular Oncology, Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, 10060 Candiolo (Torino), Italy.
2 Cancer Research and Drug Discovery, Institut de Recherches Servier, 78290 Croissy-sur-Seine, France.
3 Laboratory of Functional Genomics, The Oncogenomics Center, Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, 10060 Candiolo (Torino), Italy.
4 Division of Molecular Pharmacology and Pathophysiology, Institut de Recherches Servier, 78290 Croissy-sur-Seine, France.

* These authors contributed equally to this work.

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.

{dagger} To whom correspondence should be addressed. E-mail: livio.trusolino{at} (L.T.) and paolo.comoglio{at} (P.M.C.)

Citation: A. Bertotti, M. F. Burbridge, S. Gastaldi, F. Galimi, D. Torti, E. Medico, S. Giordano, S. Corso, G. Rolland-Valognes, B. P. Lockhart, J. A. Hickman, P. M. Comoglio, L. Trusolino, Only a Subset of Met-Activated Pathways Are Required to Sustain Oncogene Addiction. Sci. Signal. 2, ra80 (2009).

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