Single copies of mutant KRAS and mutant PIK3CA cooperate in immortalized human epithelial cells to induce tumor formation
Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude montre que des cellules ne comportant que des copies uniques des gènes mutés KRAS et PIK3CA sont susceptibles d'induire la formation d'une tumeur
The selective pressures leading to cancers with mutations in both KRAS and PIK3CA are unclear. Here we demonstrate that somatic cell knock in of both KRAS G12V and oncogenic PIK3CA mutations in human breast epithelial cells results in cooperative activation of the PI3 Kinase and MAP Kinase pathways in vitro, and leads to tumor formation in immunocompromised mice. Xenografts from double knock in cells retain single copies of mutant KRAS and PIK3CA suggesting that tumor formation does not require increased copy number of either oncogene, and these results were also observed in human colorectal cancer specimens. Mechanistically, the cooperativity between mutant KRAS and PIK3CA is mediated in part by Ras/p110 binding, as inactivating point mutations within the Ras binding domain of PIK3CA significantly abates pathway signaling. In addition, Pdk1 activation of the downstream effector p90RSK is also increased by the combined presence of mutant KRAS and PIK3CA. These results provide new insights into mutant KRAS function and its role in carcinogenesis.