Prediction of DNA Repair Inhibitor Response in Short-Term Patient-Derived Ovarian Cancer Organoids

Cancer Discov. 2018 Nov;8(11):1404-1421. doi: 10.1158/2159-8290.CD-18-0474. Epub 2018 Sep 13.

Abstract

Based on genomic analysis, 50% of high-grade serous ovarian cancers (HGSC) are predicted to have DNA repair defects. Whether this substantial subset of HGSCs actually have functional repair defects remains unknown. Here, we devise a platform for functional profiling of DNA repair in short-term patient-derived HGSC organoids. We tested 33 organoid cultures derived from 22 patients with HGSC for defects in homologous recombination (HR) and replication fork protection. Regardless of DNA repair gene mutational status, a functional defect in HR in the organoids correlated with PARP inhibitor sensitivity. A functional defect in replication fork protection correlated with carboplatin and CHK1 and ATR inhibitor sensitivity. Our results indicate that a combination of genomic analysis and functional testing of organoids allows for the identification of targetable DNA damage repair defects. Larger numbers of patient-derived organoids must be analyzed to determine whether these assays can reproducibly predict patient response in the clinic.Significance: Patient-derived ovarian tumor organoids grow rapidly and match the tumors from which they are derived, both genetically and functionally. These organoids can be used for DNA repair profiling and therapeutic sensitivity testing and provide a rapid means of assessing targetable defects in the parent tumor, offering more suitable treatment options. Cancer Discov; 8(11); 1404-21. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1333.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biomarkers, Tumor / genetics*
  • Carboplatin / administration & dosage
  • Cystadenocarcinoma, Serous / drug therapy
  • Cystadenocarcinoma, Serous / genetics
  • Cystadenocarcinoma, Serous / pathology*
  • DNA Repair / drug effects*
  • DNA Replication
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Female
  • Follow-Up Studies
  • Humans
  • Neoplasm Invasiveness
  • Neoplasm Recurrence, Local / drug therapy
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / pathology*
  • Organ Culture Techniques
  • Organoids / drug effects*
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology*
  • Prognosis
  • Pyrazines / administration & dosage
  • Pyrazoles / administration & dosage

Substances

  • Biomarkers, Tumor
  • Pyrazines
  • Pyrazoles
  • prexasertib
  • Deoxycytidine
  • gemcitabine
  • Carboplatin