Integrative ‘omic’ approaches identify a Ras/PI3K signature sustaining addiction to the MET oncogene

ABSTRACT: Tumor onset and progression require the accumulation of many genetic and epigenetic lesions. Yet, there are cases in which cancer cells rely on only one of these lesions to maintain their malignant properties, and this dependency results in tumor regression upon oncogene inactivation (‘oncogene addiction’). Determining which nodes of the many networks operative in the transformed phenotype specifically mediate this drastic response to oncogene neutralization is crucial to identify the vulnerabilities of cancer. We combined multiplex phosphoproteomics, genome-wide expression profiling, and functional assays in a variety of cancer cells addicted to tyrosine kinase receptor oncogenes, using the Met receptor as the major model system. Unexpectedly, we found that Met blockade impacts on a limited subset of Met downstream signals: little or no effect was observed for many relevant pathways controlling Met-driven neoplastic growth – such as STATs, NF-kB, JNK, and p38 MAPK – and only a restricted and pathway-specific signature of Ras/PI3K transducers and transcriptional effectors was fully neutralized. An analogous signature was also generated by EGF receptor inhibition in a different cellular context, suggesting a stereotyped response that likely does not depend on receptor type or tissue origin. Biologically, cell-cycle arrest induced by Met de-activation was recapitulated by extinction of Ras/PI3K-dependent signals and was rescued by active forms of the same signals. These findings uncover ‘dominant’ and ‘recessive’ nodes among the numerous oncogenic networks regulated by tyrosine kinase receptors and active in cancer, with the Ras/PI3K pathways being the necessary and sufficient determinants of therapeutic response.

ORGANISM(S): Homo sapiens

PROVIDER: GSE19043 | GEO | 2010/03/01

SECONDARY ACCESSION(S): PRJNA120533

REPOSITORIES: GEO