Synthetic Lethality of PARP Inhibition and Ionizing Radiation is p53-dependent
Abstract
PARP inhibitors (PARPi) are potentially effective therapeutic agents capable of inducing synthetic lethality in tumors with deficiencies in homologous recombination (HR)-mediated DNA repair such as those carrying BRCA1 mutations. However, BRCA mutations are rare, the majority of tumors are proficient in HR repair, and thus most tumors are resistant to PARPi. Previously, we observed that ionizing radiation (IR) initiates cytoplasmic translocation of BRCA1 leading to suppression of HR-mediated DNA repair and induction of synthetic PARPi lethality in wild-type BRCA1 and HR-proficient tumor cells. The tumor suppressor p53 was identified as a key factor that regulates DNA damage–induced BRCA1 cytoplasmic sequestration following IR. However, the role of p53 in IR-induced PARPi sensitization remains unclear. This study elucidates the role of p53 in IR-induced PARPi cytotoxicity in HR-proficient cancer cells and suggests p53 status may help define a patient population that might benefit from this treatment strategy. Sensitization to PARPi following IR was determined in vitro and in vivo utilizing human breast and glioma tumor cells carrying wild-type BRCA1 and p53, and in associated cells in which p53 function was modified by knockdown or mutation. In breast and glioma cells with proficient HR repair, IR-induced BRCA1 cytoplasmic sequestration, HR repair inhibition, and subsequent PARPi sensitization in vitro and in vivo was dependent upon functional p53.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 01, 2018
- Source ID
- 10.1158/1541-7786.mcr-18-0106
Entities
People
- Arnab Chakravarti
- Fen Xia
- Gina M. Sizemore
- Hao Yu
- Michael C. Ostrowski
- Rahman Mohammad
- Somaira Nowsheen
- Steven T Sizemore
Organizations
- Mayo Clinic
- Medical University of South Carolina
- National Institutes of Health
- Ohio State University
- United States Department of Defense
- University of Arkansas for Medical Sciences
- Virginia Commonwealth University