A HUWE1 defect causes PARP inhibitor resistance by modulating the BRCA1-∆11q splice variant

Oncogene. 2023 Sep;42(36):2701-2709. doi: 10.1038/s41388-023-02782-8. Epub 2023 Jul 25.

Abstract

Although PARP inhibitors (PARPi) now form part of the standard-of-care for the treatment of homologous recombination defective cancers, de novo and acquired resistance limits their overall effectiveness. Previously, overexpression of the BRCA1-∆11q splice variant has been shown to cause PARPi resistance. How cancer cells achieve increased BRCA1-∆11q expression has remained unclear. Using isogenic cells with different BRCA1 mutations, we show that reduction in HUWE1 leads to increased levels of BRCA1-∆11q and PARPi resistance. This effect is specific to cells able to express BRCA1-∆11q (e.g. BRCA1 exon 11 mutant cells) and is not seen in BRCA1 mutants that cannot express BRCA1-∆11q, nor in BRCA2 mutant cells. As well as increasing levels of BRCA1-∆11q protein in exon 11 mutant cells, HUWE1 silencing also restores RAD51 nuclear foci and platinum salt resistance. HUWE1 catalytic domain mutations were also seen in a case of PARPi resistant, BRCA1 exon 11 mutant, high grade serous ovarian cancer. These results suggest how elevated levels of BRCA1-∆11q and PARPi resistance can be achieved, identify HUWE1 as a candidate biomarker of PARPi resistance for assessment in future clinical trials and illustrate how some PARPi resistance mechanisms may only operate in patients with particular BRCA1 mutations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / pharmacology
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism
  • BRCA2 Protein / genetics
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Humans
  • Mutation
  • Neoplasms* / drug therapy
  • Ovarian Neoplasms* / drug therapy
  • Ovarian Neoplasms* / genetics
  • Ovarian Neoplasms* / metabolism
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use
  • Tumor Suppressor Proteins / genetics
  • Ubiquitin-Protein Ligases / genetics

Substances

  • Poly(ADP-ribose) Polymerase Inhibitors
  • Antineoplastic Agents
  • BRCA1 Protein
  • BRCA2 Protein
  • BRCA1 protein, human
  • HUWE1 protein, human
  • Tumor Suppressor Proteins
  • Ubiquitin-Protein Ligases