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Cytidine deaminases APOBEC3C and APOBEC3D promote DNA replication stress resistance in pancreatic cancer cells

Tajinder Ubhi1,2, Olga Zaslaver2, Andrew T Quaile2

  • 1Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.

Nature Cancer
|March 6, 2024
PubMed

Insights

Gemcitabine resistance in pancreatic cancer is reduced by targeting APOBEC3C and APOBEC3D. These cytidine deaminases help cancer cells survive gemcitabine treatment by aiding DNA repair.

Area of Science:

  • Cancer Biology
  • Genetics
  • Molecular Oncology

Background:

  • Gemcitabine is a key chemotherapy for pancreatic ductal adenocarcinoma (PDAC).
  • Tumor resistance limits gemcitabine's effectiveness in PDAC.
  • Understanding cancer cell responses to gemcitabine is crucial for improving treatment.

Purpose of the Study:

  • To identify genetic factors influencing cancer cell response to gemcitabine in PDAC.
  • To investigate the role of cytidine deaminases APOBEC3C and APOBEC3D in gemcitabine resistance.

Main Methods:

  • Genome-scale CRISPR-Cas9 chemical-genetic screens were conducted in PDAC cells.
  • Analysis of cell fitness and DNA replication stress resistance following gemcitabine treatment.
  • Validation in PDAC cell lines, organoids, and xenografts.

Main Results:

  • Disruption of APOBEC3C and APOBEC3D led to a selective loss of cell fitness in PDAC cells treated with gemcitabine.
  • APOBEC3C and APOBEC3D enhance DNA replication stress resistance and survival by deaminating nuclear cytidines, promoting replication fork restart and repair.
  • The interaction between APOBEC3C/APOBEC3D and gemcitabine was specific to PDAC cells, not observed in non-transformed cells.

Conclusions:

  • APOBEC3C and APOBEC3D play significant roles in conferring DNA replication stress resistance in PDAC cells.
  • These cytidine deaminases are key mediators of gemcitabine resistance in pancreatic cancer.
  • Targeting APOBEC3C and APOBEC3D presents a potential strategy to enhance gemcitabine-based therapies for PDAC.

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