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Targeting the nucleotide salvage factor DNPH1 sensitizes BRCA-deficient cells to PARP inhibitors

Kasper Fugger1, Ilirjana Bajrami2, Mariana Silva Dos Santos2

  • 1The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. stephen.west@crick.ac.uk kasper.fugger@crick.ac.uk.

Science (New York, N.Y.)
|April 9, 2021
PubMed

Insights

Targeting DNPH1 enhances cancer therapy for BRCA-deficient patients. Inhibiting DNPH1 boosts sensitivity to PARP inhibitors (PARPi) by increasing cytotoxic nucleotide levels, leading to cancer cell death.

Area of Science:

  • Genetics and Genomics
  • Cancer Biology
  • Drug Discovery

Background:

  • BRCA1/BRCA2 mutations increase breast and ovarian cancer risk.
  • Poly(ADP-ribose) polymerase inhibitors (PARPi) are used to treat these cancers.

Purpose of the Study:

  • To investigate if inhibiting DNPH1 can enhance the efficacy of PARPi in BRCA-deficient cancers.
  • To explore the mechanism of synthetic lethality induced by DNPH1 inhibition and PARPi.

Main Methods:

  • Utilizing cell culture models of BRCA-deficient cancers.
  • Employing DNPH1 inhibition and 5-hydroxymethyl-deoxyuridine (hmdU) treatment.
  • Assessing sensitivity to PARP inhibitors (PARPi) and analyzing DNA damage response pathways.

Main Results:

  • DNPH1 inhibition potentiates PARPi sensitivity in BRCA-deficient cells.
  • Genomic accumulation of hmdU triggers synthetic lethality via PARP trapping and replication fork collapse.
  • DNPH1 inhibition resensitizes PARPi-resistant cells.

Conclusions:

  • DNPH1 inhibition is a promising strategy to potentiate PARPi therapy in BRCA-deficient cancers.
  • Targeting DNPH1 offers a novel approach to overcome PARPi resistance.

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