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A Genetic Progression Model of BrafV600E-Induced Intestinal Tumorigenesis Reveals Targets for Therapeutic Intervention

2013; Cell Press; Volume: 24; Issue: 1 Linguagem: Inglês

10.1016/j.ccr.2013.05.014

1878-3686

Roland Rad, Juan Cadiñanos, Lena Rad, Ignacio Varela, Alexander Strong, Lydia Kriegl, Fernando Constantino‐Casas, Stefan Eser, Maren Hieber, Barbara Seidler, Stacey Price, Mario F. Fraga, Vincenzo Calvanese, Gary J. Hoffman, Hannes Ponstingl, Günter Schneider, Kosuke Yusa, Carolyn Grove, Roland M. Schmid, Wei Wang, George S. Vassiliou, Thomas Kirchner, Ultan McDermott, Pentao Liu, Dieter Saur, Allan Bradley,

Genetic factors in colorectal cancer

We show that BRAFV600E initiates an alternative pathway to colorectal cancer (CRC), which progresses through a hyperplasia/adenoma/carcinoma sequence. This pathway underlies significant subsets of CRCs with distinctive pathomorphologic/genetic/epidemiologic/clinical characteristics. Genetic and functional analyses in mice revealed a series of stage-specific molecular alterations driving different phases of tumor evolution and uncovered mechanisms underlying this stage specificity. We further demonstrate dose-dependent effects of oncogenic signaling, with physiologic BrafV600E expression being sufficient for hyperplasia induction, but later stage intensified Mapk-signaling driving both tumor progression and activation of intrinsic tumor suppression. Such phenomena explain, for example, the inability of p53 to restrain tumor initiation as well as its importance in invasiveness control, and the late stage specificity of its somatic mutation. Finally, systematic drug screening revealed sensitivity of this CRC subtype to targeted therapeutics, including Mek or combinatorial PI3K/Braf inhibition.