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Visualizing DNA Damage Repair Proteins in Patient-Derived Ovarian Cancer Organoids via Immunofluorescence Assays
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Identifying and Overcoming Mechanisms of PARP Inhibitor Resistance in Homologous Recombination Repair-Deficient and

Miriam K Gomez1, Giuditta Illuzzi2, Carlota Colomer2

  • 1Nicola Murray Centre for Ovarian Cancer Research, Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.

Cancers
|June 13, 2020
PubMed

Insights

Poly (ADP-ribose) polymerase (PARP) inhibitors improve ovarian cancer treatment, but resistance occurs. Targeting WEE1 kinase with AZD1775 may overcome PARP inhibitor resistance in high-grade serous ovarian cancer (HGSOC) by inactivating the G2 checkpoint.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • High-grade serous ovarian cancer (HGSOC) poses a significant mortality risk for women.
  • Poly (ADP-ribose) polymerase (PARP) inhibitors offer improved treatment for HRR-deficient HGSOC, but resistance limits efficacy.
  • Some HRR-proficient cancers also respond to PARP inhibitors, indicating diverse resistance mechanisms.

Purpose of the Study:

  • To compare olaparib resistance mechanisms in HRR-proficient and HRR-deficient HGSOC.
  • To investigate overcoming resistance in HGSOC, considering its high TP53 mutation rate and G2 checkpoint reliance.
  • To identify therapeutic strategies for PARP inhibitor resistance in ovarian cancer.

Main Methods:

  • Analysis of resistance mechanisms to olaparib in HGSOC models.
  • Identification of molecular alterations contributing to PARP inhibitor resistance.
  • Evaluation of WEE1 kinase inhibitor AZD1775 in controlling resistant HGSOC clones.

Main Results:

  • Alterations in multiple resistance factors were found in both HRR-proficient and -deficient HGSOC.
  • Reduced poly (ADP-ribose) glycohydrolase (PARG) levels were a frequent change, potentially preserving DNA damage response.
  • WEE1 kinase inhibitor AZD1775 controlled the growth of all isolated olaparib-resistant clones by inactivating the G2 checkpoint.

Conclusions:

  • PARP inhibitor resistance in HGSOC involves alterations in DNA repair and damage response pathways.
  • WEE1 kinase inhibition presents a potential therapeutic strategy to overcome olaparib resistance in HGSOC.
  • AZD1775 may offer a viable treatment option for patients developing resistance to PARP inhibitors.
Keywords:
DNA repairPARP inhibitorWEE1 kinaseolaparibovarian cancerresistance mechanism

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