Prediction of DNA Repair Inhibitor Response in Short-Term Patient-Derived Ovarian Cancer Organoids
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 01, 2018
- Source ID
- 10.1158/2159-8290.cd-18-0474
Entities
People
- Alan D'Andrea
- Bose S. Kochupurakkal
- Brennan Decker
- Christopher P Crum
- Chunyu Yang
- Colleen Feltmate
- Elizabeth M Swisher
- Emma A Roberts
- Geoffrey I. Shapiro
- Ha-Thanh Nguyen
- Joseph V. Bonventre
- Joyce F. Liu
- Khanh T. Do
- Marisa R. Nucci
- Michael G. Muto
- Michael J. Worley Jr
- Neil S Horowitz
- Panagiotis A Konstantinopoulos
- Ross S. Berkowitz
- Ryuji Morizane
- Sarah J. Hill
- Ursula A. Matulonis
Organizations
- Brigham and Women's Hospital
- Dana–Farber Cancer Institute
- Harvard Medical School
- Leukemia & Lymphoma Society
- National Cancer Institute
- National Heart, Lung, and Blood Institute
- Richard and Susan Smith Family Foundation
- Stand Up to Cancer
- The Breast Cancer Research Foundation
- United States Department of Defense
- University of Washington