Abstract
Mammalian target of rapamycin complex 1 (mTORC1) is frequently activated in human cancers; however, clinical trials of rapalog (the mTORC1 inhibitors) have shown that pancreatic ductal adenocarcinomas (PDACs) resist to the treatment. Rapalog treatment activated the extracellular signal-regulated kinase (ERK) pathway in K-Ras mt PDAC cells. K-Ras knockdown abolished the insulin-like growth factor-1 (IGF-1)-induced ERK pathway in the K-Ras mt PDAC cells and enhanced the therapeutic efficacy of everolimus in treating K-Ras mt PDAC cells-derived mouse xenografts. The results indicate that targeting of K-Ras mutation may lead to the development of therapies that overcome rapalog resistance in PDAC.
Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adenocarcinoma / drug therapy*
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Adenocarcinoma / genetics
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Animals
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Antineoplastic Agents / pharmacology
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Benzenesulfonates / pharmacology
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Carcinoma, Pancreatic Ductal / drug therapy*
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Carcinoma, Pancreatic Ductal / genetics
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Cell Line, Tumor
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Drug Resistance, Neoplasm
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Enzyme Activation
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Everolimus
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Extracellular Signal-Regulated MAP Kinases / physiology*
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Feedback, Physiological
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Female
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Humans
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Insulin-Like Growth Factor I / pharmacology*
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MAP Kinase Signaling System / physiology
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Multiprotein Complexes
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Mutation*
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Niacinamide / analogs & derivatives
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Pancreatic Neoplasms / drug therapy*
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Pancreatic Neoplasms / genetics
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Phenylurea Compounds
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Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins p21(ras)
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Pyridines / pharmacology
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Pyrimidines / pharmacology
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Pyrroles / pharmacology
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Sirolimus / analogs & derivatives
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Sirolimus / pharmacology
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Sorafenib
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TOR Serine-Threonine Kinases
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Xenograft Model Antitumor Assays
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ras Proteins / genetics*
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ras Proteins / physiology
Substances
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Antineoplastic Agents
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Benzenesulfonates
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KRAS protein, human
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Multiprotein Complexes
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NVP-AEW541
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Phenylurea Compounds
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Proteins
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Proto-Oncogene Proteins
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Pyridines
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Pyrimidines
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Pyrroles
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Niacinamide
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Insulin-Like Growth Factor I
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Everolimus
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Sorafenib
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Mechanistic Target of Rapamycin Complex 1
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TOR Serine-Threonine Kinases
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Extracellular Signal-Regulated MAP Kinases
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Proto-Oncogene Proteins p21(ras)
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ras Proteins
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Sirolimus