title: K-Ras mutation-mediated IGF-1-induced feedback ERK activation contributes to the rapalog resistance in pancreatic ductal adenocarcinomas.
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.
authors.affiliation: Department of Hepatobiliary & Pancreas Surgery and Hematology & Oncology, The First Hospital, Jilin University, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Wei
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Anita C
authors.initials: AC
authors.lastname: Bellail
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Olson
authors.forename: Shi-Yong
authors.initials: SY
authors.lastname: Sun
authors.forename: Guoyue
authors.initials: G
authors.lastname: Lu
authors.forename: Lijuan
authors.initials: L
authors.lastname: Ding
authors.forename: Changji
authors.initials: C
authors.lastname: Yuan
authors.forename: Guangyi
authors.initials: G
authors.lastname: Wang
authors.forename: Chunhai
authors.initials: C
authors.lastname: Hao
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001557:Benzenesulfonates / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D000068338:Everolimus; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D025461:Feedback, Physiological; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D009154:Mutation; D009536:Niacinamide / Q000031:analogs & derivatives; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D010671:Phenylurea Compounds; D011506:Proteins / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras); D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics* / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; C117307:KRAS protein, human; D046912:Multiprotein Complexes; C501177:NVP-AEW541; D010671:Phenylurea Compounds; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D009536:Niacinamide; D007334:Insulin-Like Growth Factor I; D000068338:Everolimus; D000077157:Sorafenib; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D020123:Sirolimus