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584 Overcoming resistance to PARP inhibitor in ovarian cancer with BRCA2 reversion mutation
  1. Nawel Zouggari1,2,
  2. Wenwen Wang3,
  3. Sana Intidhar Labidi Galy5,6 and
  4. Thanos Halazonetis6
  1. 1Faculty of Medicine, Geneva, Switzerland
  2. 2Faculty of Sciences, Geneva, Switzerland
  3. 3Department of Medicine, Geneva, Switzerland
  4. 4Department of Molecular Biology
  5. 5Division of Oncology, Geneva, Switzerland
  6. 6University of Geneva, Geneva, Switzerland


Introduction/Background High-grade serous ovarian cancer (HGSOC) is the most frequent histological subtype of ovarian cancer, the deadliest gynecological cancer. It is characterized by defects in homologous recombination (HR) in up to 50% of the cases, mainly through BRCA1/2 mutations. BRCA1/2 mutated tumors are extremely sensitive to platinum and PARP inhibitors (PARPi). Nevertheless, the majority of tumors will ultimately acquire drug resistance leading to death. Reversion mutations of BRCA1/2 restoring the open-reading frame is the most frequent mechanism of resistance to PARPi in human tumors. Few therapeutic options are available at this stage of the disease.

Methodology We conducted high-throughput gene silencing screen RNA that target DNA damage response genes on paired BRCA2 mutated HGSOC cell lines (PEO1 and PEO4) to uncover new synthetically lethal genes in tumor cells with BRCA2 reversion mutation. Top hit genes were validated by siRNAs and small molecules on cell lines and a large collection of clinically and genomically annotated HGSOC patient’s derived organoids.

Results Among top hits, RNA silencing of CCDC155, a component of the LINC (linker of nucleoskeleton and cytoskeleton) showed significant accumulation of DNA damage, likely reflecting key functions in DNA repair pathway, and was synthetically lethal when combined with olaparib in cell lines with BRCA2 reversion mutation.

Conclusion CCDC155 is synthetically lethal in tumor cells with BRCA2 reversion mutation. We are currently validating other top hits. An update of the ongoing experiments will be presented at the ESGO meeting.

Disclosures SILG received consulting fees from AstraZeneca and travelling expenses from AstraZeneca and Pharmamar. TH is co-founder of FoRx Therapeutics AG.

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