Abstract
RAS proteins directly activate PI3-kinases. Mice bearing a germline mutation in the RAS binding domain of the p110α 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.
Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / drug therapy
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Adenocarcinoma / enzymology*
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Adenocarcinoma / pathology
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Animals
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Antineoplastic Agents, Hormonal / pharmacology
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Class I Phosphatidylinositol 3-Kinases / chemistry
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Class I Phosphatidylinositol 3-Kinases / genetics
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Class I Phosphatidylinositol 3-Kinases / metabolism*
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Disease Progression
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Humans
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Lung / pathology
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Lung Neoplasms / drug therapy
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Lung Neoplasms / enzymology*
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Lung Neoplasms / pathology
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MAP Kinase Signaling System / drug effects
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mutation
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Protein Binding
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Protein Interaction Domains and Motifs
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Proto-Oncogene Proteins p21(ras) / genetics*
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Proto-Oncogene Proteins p21(ras) / metabolism
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Pyridones / pharmacology
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Pyrimidinones / pharmacology
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Tamoxifen / pharmacology
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Tumor Burden
Substances
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Antineoplastic Agents, Hormonal
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Pyridones
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Pyrimidinones
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Tamoxifen
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trametinib
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1-phosphatidylinositol 3-kinase p110 subunit, mouse
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Class I Phosphatidylinositol 3-Kinases
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Mitogen-Activated Protein Kinases
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Hras protein, mouse
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Proto-Oncogene Proteins p21(ras)