Co-dependency between KRAS addiction and ARHGEF2 promotes an adaptive escape from MAPK pathway inhibition

Small GTPases. 2019 Nov;10(6):441-448. doi: 10.1080/21541248.2017.1337545. Epub 2017 Jul 11.


Oncogenic KRAS engages multiple effector pathways including the MAPK cascade to promote proliferation and survival of pancreatic cancer cells. KRAS-transformed cancer cells exhibit oncogene addiction to sustained activity of RAS for maintenance of malignant phenotypes. Previously, we have shown an essential role for the RHO guanine exchange factor ARHGEF2 for growth and survival of RAS-transformed pancreatic tumors. Here, we have determined that pancreatic cancer cells demonstrating KRAS addiction are significantly dependent on expression of ARHGEF2. Furthermore, enforced expression of ARHGEF2 desensitizes cells to pharmacological MEK inhibition and initiates a positive feedback loop which activates ERK phosphorylation and the downstream ARHGEF2 promoter. Therefore, targeting ARHGEF2 expression may increase the efficacy of MAPK inhibitors for treatment of RAS-dependent pancreatic cancers.

Keywords: ARHGEF2; GEF-H1; KRAS; MEK inhibition; Ras dependency; oncogene addiction; pancreatic cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Humans
  • MAP Kinase Signaling System
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Rho Guanine Nucleotide Exchange Factors / genetics*
  • Rho Guanine Nucleotide Exchange Factors / metabolism


  • Rho Guanine Nucleotide Exchange Factors
  • Proto-Oncogene Proteins p21(ras)

Grant support