Abstract
Gastric cancer is one of the most virulent malignant diseases and is the second leading cause of cancer mortality in the world. The receptor tyrosine kinase MET is constitutively activated in many gastric cancers and its expression is strictly required for survival of some gastric cancer cells. Targeting gastric cancers with amplified or abnormally activated MET may have therapeutic benefit based on nonclinical and emerging clinical findings. However, one of the major problems of therapies targeting tyrosine kinases is that many tumors are not responsive to treatment or eventually develop resistance to the drugs. This study aims to understand the mechanisms of MET resistance in gastric SNU-5 xenografts which developed resistance to PHA665752, a MET inhibitor, through long-period tyrosine kinase inhibitor exposure. In the current study, we found that PI3K p110α is overexpressed in PHA665752-resistant SNU-5 xenografts. These findings showed that high PI3K p110α expression contributes to tyrosine kinase inhibitor resistance. In addition, we reported the development of a carcinogen-induced gastric cancer model that recapitulates PI3K p110α expression in human disease, which will serve as a useful model to study PI3K p110α's biology and its effectiveness as a novel biomarker and a molecular target for gastric cancer. Ultimately, PI3K p110α represents a novel target for gastric cancer.
Keywords:
MET; PI3K p110α; SNU-5; gastric cancer; tyrosine kinase inhibitor resistance.
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Carcinoma / drug therapy*
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Carcinoma / enzymology
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Carcinoma / genetics
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Carcinoma / pathology
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Cell Line, Tumor
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Class I Phosphatidylinositol 3-Kinases
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Drug Resistance, Neoplasm* / genetics
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Female
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Furans / pharmacology
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Gene Expression Regulation, Enzymologic
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Gene Expression Regulation, Neoplastic
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Humans
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Indoles / pharmacology*
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Mice, Inbred BALB C
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Mice, Nude
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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 / pharmacology*
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Proto-Oncogene Proteins c-met / antagonists & inhibitors*
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Proto-Oncogene Proteins c-met / genetics
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Proto-Oncogene Proteins c-met / metabolism
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Pyridines / pharmacology
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Pyrimidines / pharmacology
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Stomach Neoplasms / drug therapy*
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Stomach Neoplasms / enzymology
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Stomach Neoplasms / genetics
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Stomach Neoplasms / pathology
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Sulfones / pharmacology*
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Time Factors
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Tumor Burden / drug effects
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Up-Regulation
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Xenograft Model Antitumor Assays
Substances
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5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one
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Antineoplastic Agents
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Furans
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Indoles
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PI103
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Pyridines
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Pyrimidines
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Sulfones
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Class I Phosphatidylinositol 3-Kinases
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PIK3CA protein, human
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MET protein, human
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Proto-Oncogene Proteins c-met