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TRIP13 protects pancreatic cancer cells against intrinsic and therapy-induced DNA replication stress

Jay R Anand1, Gaith N Droby2, Sayali Joseph1

  • 1Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States.

NAR Cancer
|March 21, 2025
PubMed

Insights

Oncogene activation causes DNA replication stress, requiring DNA damage response (DDR) for survival. We found TRIP13 is essential for KRAS-mutant pancreatic cancer cells, offering a new therapeutic target.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • Oncogene activation in normal cells triggers DNA replication stress, creating a dependency on DNA damage response (DDR) pathways for survival.
  • The DDR is pathologically altered in various cancers, with distinct oncogenic stimuli employing unique signaling mechanisms.
  • Mutant KRAS drives 90% of pancreatic ductal adenocarcinomas (PDACs), highlighting the need to understand KRAS-induced DDR in this cancer.

Purpose of the Study:

  • To investigate the DDR mechanisms that enable tolerance of KRAS-induced DNA replication stress in normal human pancreatic epithelial cells (HPNE cells).
  • To identify novel DDR players involved in KRAS-driven pancreatic cancer.
  • To explore TRIP13 as a potential therapeutic vulnerability in KRAS-mutant PDAC.

Main Methods:

  • Candidate screening approach to identify KRAS-induced genes.
  • Genetic and pharmacological tools to assess TRIP13 function in KRASG12V-expressing HPNE cells.
  • Evaluation of homologous recombination (HR) dependency and sensitivity to genotoxic agents and inhibitors in TRIP13-depleted cells and PDAC cell lines.

Main Results:

  • TRIP13 mRNA is upregulated by KRASG12V and highly expressed in PDAC compared to normal tissues.
  • TRIP13 is essential for DNA synthesis and viability in KRASG12V-expressing cells.
  • TRIP13 depletion in KRASG12V-expressing cells leads to HR deficiency phenotypes and sensitivity to translesion synthesis and PARP inhibitors.
  • TRIP13 depletion sensitizes established PDAC cell lines to DNA damage and genotoxic therapies.

Conclusions:

  • TRIP13 is a KRASG12V-induced gene crucial for maintaining DNA synthesis and survival in KRAS-mutant pancreatic cells.
  • TRIP13 functions in a homologous recombination-dependent manner, and its depletion confers sensitivity to HR deficiency-associated liabilities.
  • TRIP13 represents a novel and therapeutically actionable vulnerability in KRAS-mutant pancreatic ductal adenocarcinoma.

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