K-Ras mutation-mediated IGF-1-induced feedback ERK activation contributes to the rapalog resistance in pancreatic ductal adenocarcinomas

Cancer Lett. 2012 Sep 1;322(1):58-69. doi: 10.1016/j.canlet.2012.02.005. Epub 2012 Feb 14.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / genetics
  • Animals
  • Antineoplastic Agents / pharmacology
  • Benzenesulfonates / pharmacology
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / genetics
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Enzyme Activation
  • Everolimus
  • Extracellular Signal-Regulated MAP Kinases / physiology*
  • Feedback, Physiological
  • Female
  • Humans
  • Insulin-Like Growth Factor I / pharmacology*
  • MAP Kinase Signaling System / physiology
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Multiprotein Complexes
  • Mutation*
  • Niacinamide / analogs & derivatives
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / genetics
  • Phenylurea Compounds
  • Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / physiology
  • Proto-Oncogene Proteins p21(ras)
  • Pyridines / pharmacology
  • Pyrimidines / pharmacology
  • Pyrroles / pharmacology
  • Sirolimus / analogs & derivatives
  • Sirolimus / pharmacology
  • Sorafenib
  • TOR Serine-Threonine Kinases
  • Xenograft Model Antitumor Assays
  • ras Proteins / genetics*
  • ras Proteins / physiology

Substances

  • Antineoplastic Agents
  • Benzenesulfonates
  • KRAS protein, human
  • Multiprotein Complexes
  • NVP-AEW541
  • Phenylurea Compounds
  • Proteins
  • Proto-Oncogene Proteins
  • Pyridines
  • Pyrimidines
  • Pyrroles
  • Niacinamide
  • Insulin-Like Growth Factor I
  • Everolimus
  • Sorafenib
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins
  • Sirolimus