Lack of synergy between AR-targeted therapies and PARP inhibitors in homologous recombination–proficient prostate cancer
Abstract
Recent clinical trials have explored the combination of androgen receptor (AR) pathway inhibitors and poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors as a potential treatment for castration-resistant prostate cancer. This combination treatment is based on the premise that AR directly regulates expression of DNA repair genes, leading to synergy between PARP and AR inhibition. Despite some promising preclinical evidence, this combination therapy has shown limited efficacy in patients with homologous recombination (HR)–proficient tumors. To investigate this discrepancy between preclinical and clinical results, we profiled the effects of PARP inhibition in prostate cancer models in the presence or absence of AR inhibition. Surprisingly, AR inhibition impaired response to PARP inhibitors in castration-sensitive cells and had no effect on response in castration-resistant cells. AR inhibition also did not regulate DNA repair in either the castration-resistant or castration-sensitive setting. Instead, we find that cell cycle progression is required for response to PARP inhibition in homologous recombination–proficient prostate cancer.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (16)
Nicole A. Traphagen
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School
Esmé Wheeler
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School
Rong Li
Tara Akhshi
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School
Ramya Ravindranathan
Department of Radiation Oncology, Dana-Farber Cancer Institute and Harvard Medical School
Christian Alfieri
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School
Feng Lu
Department of Medical Oncology, Dana-Farber Cancer Institute
Buraq Ahmed
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School
Alok K. Tewari
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School
Steven P. Balk
Department of Medicine, Beth Israel Deaconess Medical Center
Peter S. Nelson
Division of Hematology and Oncology, University of Washington, Fred Hutchinson Cancer Center
Eva Corey
Department of Urology, University of Washington
Henry Long
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School
Alan D. D’Andrea
Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School
Xintao Qiu
Department of Medical Oncology, Dana-Farber Cancer Institute
Myles Brown
Department of Medical Oncology, Dana-Farber Cancer Institute