Requirement for Interaction of PI3-Kinase p110
Menée à l'aide d'un modèle murin, cette étude met en évidence des mécanismes suggérant l'intérêt d'inhiber l'interaction entre la sous-unité p110
RAS proteins directly activate PI3-kinases. Mice bearing a germline mutation in the RAS binding domain of the p110
α subunit of PI3-kinse are resistant to the development of RAS-driven tumors. However, it is unknown whether interaction of RAS with PI3-kinase is required in established tumors. The need for RAS interaction with p110α in the maintenance of mutant Kras-driven lung tumors was explored using an inducible mouse model. In established tumors, removal of the ability of p110α to interact with RAS causes long-term tumor stasis and partial regression. This is a tumor cell-autonomous effect, which is improved significantly by combination with MEK inhibition. Total removal of p110α expression or activity has comparable effects, albeit with greater toxicities.
"Inducible disruption of PI3-kinase p110
α interaction with RAS was modeled in mice
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Blocking RAS/p110α interaction in established lung tumors causes partial regression
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Blocking RAS/p110α binding has effects similar to p110α deletion on tumor regression
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Coordinate MEK inhibition is required for major regression of Kras mutant lung cancer
Cancer cell , article en libre accès, 2012