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

Feng Wei, Yan Liu, Anita Bellail, Jeffrey J. Olson, Shi Yong Sun, Guoyue Lu, Lijuan Ding, Changji Yuan, Guangyi Wang, Chunhai Hao

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)58-69
Number of pages12
JournalCancer Letters
Volume322
Issue number1
DOIs
StatePublished - Sep 1 2012
Externally publishedYes

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Extracellular Signal-Regulated MAP Kinases
Somatomedins
Adenocarcinoma
Mutation
Mitogen-Activated Protein Kinase 3
Heterografts
Clinical Trials
Therapeutics
Neoplasms
mechanistic target of rapamycin complex 1

Keywords

  • ERK
  • K-Ras
  • MTORC1
  • Pancreatic cancer
  • Rapalog

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

K-Ras mutation-mediated IGF-1-induced feedback ERK activation contributes to the rapalog resistance in pancreatic ductal adenocarcinomas. / Wei, Feng; Liu, Yan; Bellail, Anita; Olson, Jeffrey J.; Sun, Shi Yong; Lu, Guoyue; Ding, Lijuan; Yuan, Changji; Wang, Guangyi; Hao, Chunhai.

In: Cancer Letters, Vol. 322, No. 1, 01.09.2012, p. 58-69.

Research output: Contribution to journalArticle

Wei, Feng ; Liu, Yan ; Bellail, Anita ; Olson, Jeffrey J. ; Sun, Shi Yong ; Lu, Guoyue ; Ding, Lijuan ; Yuan, Changji ; Wang, Guangyi ; Hao, Chunhai. / K-Ras mutation-mediated IGF-1-induced feedback ERK activation contributes to the rapalog resistance in pancreatic ductal adenocarcinomas. In: Cancer Letters. 2012 ; Vol. 322, No. 1. pp. 58-69.
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