RET, a targetable driver of pancreatic adenocarcinoma

Moran Amit, Shorook Na'ara, Eran Fridman, Euvgeni Vladovski, Tanya Wasserman, Neta Milman, Ziv Gil

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

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 p53 R172H 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/Kras G12D /p53 R172H (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.

Original languageEnglish (US)
Pages (from-to)3014-3022
Number of pages9
JournalInternational Journal of Cancer
Volume144
Issue number12
DOIs
StatePublished - Jun 15 2019

Keywords

  • GDNF
  • RET
  • SNP
  • pancreatic ductal adenocarcinoma
  • tumorigenesis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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