RET, a targetable driver of pancreatic adenocarcinoma

Int J Cancer. 2019 Jun 15;144(12):3014-3022. doi: 10.1002/ijc.32040. Epub 2019 Jan 11.


Pancreatic ductal adenocarcinoma (PDA) remains a deadly disease, affecting about 40,000 individuals in the United States annually. We aimed to characterize the role of RET as a co-driver of pancreas tumorigenesis. To assess the role of RET as a co-driver of PDA, we generated a novel triple mutant transgenic mouse based on the cre-activated p53R172H gene and a constitutively active RET M919T mutant (PRC). Survival analysis was performed using Kaplan-Meier analysis. Study of human PDA specimens and Pdx-1-Cre/KrasG12D /p53R172H (KPC) mice revealed that RET is upregulated during pancreas tumorigenesis, from inception through precursor lesions, to invasive cancer. We demonstrated that activation of RET is capable of inducing invasive pancreatic carcinomas in the background of the P53 inactivation mutation. Compared to KPC mice, PRC animals had distinct phenotypes, including longer latency to tumor progression, longer survival, and the presence of multiple macrometastases. Enhanced activation of the MAPK pathway was observed as early as the PanIN 2 stage. Sequencing of the exonic regions of KRAS in PRC-derived PDA cells revealed no evidence of KRAS mutations. RET can be an essential co-driver of pancreatic tumorigenesis in conjugation with KRAS activity. These data suggest that RET may be a potential target in the treatment of PDA.

Keywords: GDNF; RET; SNP; pancreatic ductal adenocarcinoma; tumorigenesis.

MeSH terms

  • Animals
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Carcinoma, Pancreatic Ductal / enzymology*
  • Carcinoma, Pancreatic Ductal / pathology
  • Enzyme Activation
  • Female
  • Humans
  • MAP Kinase Signaling System
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Pancreatic Neoplasms / enzymology*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology
  • Proto-Oncogene Proteins c-ret / genetics
  • Proto-Oncogene Proteins c-ret / metabolism*
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Up-Regulation


  • KRAS protein, human
  • Proto-Oncogene Proteins c-ret
  • RET protein, human
  • Ret protein, mouse
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)