Abstract
Previous genetic analyses have suggested that mutations of the genes encoding PI3Kα facilitate invasion and metastasis but have less effect on primary tumor growth. These findings have major implications for therapeutics but have not been factored into pre-clinical drug development designs. Here we show that the inhibition of PI3Kα by newly designed small molecule inhibitors prevented metastasis formation in mice but had much less effect on the growth of subcutaneous xenografts or primary intra-abdominal tumors. These data support the idea that PI3Kα plays an important role in the metastatic process and suggest a more informed strategy for selecting drugs worthy of further development for clinical application.
Keywords:
PI3K; metastasis; small molecule inhibitor.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Proliferation / drug effects
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Class I Phosphatidylinositol 3-Kinases
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Colorectal Neoplasms / drug therapy*
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Colorectal Neoplasms / enzymology
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / pathology
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Dose-Response Relationship, Drug
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Drug Design
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Female
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HCT116 Cells
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Humans
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Liver Neoplasms / enzymology
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Liver Neoplasms / genetics
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Liver Neoplasms / prevention & control*
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Liver Neoplasms / secondary
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Lung Neoplasms / enzymology
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Lung Neoplasms / genetics
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Lung Neoplasms / prevention & control*
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Lung Neoplasms / secondary
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Mice
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Mice, Inbred NOD
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Mice, Nude
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Molecular Targeted Therapy
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Mutation
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Neoplasm Invasiveness
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors*
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Structure-Activity Relationship
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Time Factors
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Class I Phosphatidylinositol 3-Kinases
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PIK3CA protein, human