Prediction of DNA Repair Inhibitor Response in Short Term Pa

• Based on genomic analysis, fifty percent 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 functionally profiling DNA repair in short-term patient-derived HGSC organoids. We tested 33 organoid cultures derived from 22 HGSC patients 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.

  Received May 3, 2018.

  Revision received August 15, 2018.

  Accepted September 5, 2018.

  Copyright ©2018, American Association for Cancer Research.