The emerging role of homologous recombination repair and PARP inhibitors in genitourinary malignancies.
As cells age and are exposed to genotoxic stress, preservation of the genomic code requires multiple DNA repair pathways to remove single-strand or double-strand breaks. Loss of function somatic genomic aberrations or germline deficiency in genes involved in DNA repair can result in acute cell death or, after a latency period, cellular transformation. Therapeutic exploitation of DNA repair by inhibition of poly (adenosine diphosphate [ADP]) ribose polymerases (PARP), a family of enzymes involved in the repair of single-strand and in some cases double-strand breaks, has become a novel cancer treatment. Although the application of PARP inhibitors (PARPis) initially focused on tumors with BRCA1 or BRCA2 deficiencies, synthetic susceptibilities to PARPis have been expanded due to the identification of tumors with mutations pathways involved in DNA damage repair, in particular those that repair double-strand breaks using homologous recombination (HR). There is an increasing appreciation that genitourinary (GU) malignancies, including bladder cancer and especially prostate cancer, contain subsets of patients with germline and somatic alterations in HR genes that may reflect an increased response to PARPis. In this review, the authors describe the mechanisms and rationale of the use of PARPis in patients with GU cancers, summarize previously reported preclinical and clinical trials, and identify ongoing trials to determine how PARPis and strategies targeted at HR repair can have widespread application in patients with GU cancers. Cancer 2017;123:1912-1924. © 2017 American Cancer Society.
Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
Kalen J
KJ
Rimar
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Phuoc T
0000-0002-0147-0376
PT
Tran
Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
Richard S
RS
Matulewicz
Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
Maha
M
Hussain
Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
Joshua J
JJ
Meeks
D001562:Benzimidazoles / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics; D010793:Phthalazines / Q000627:therapeutic use; D010879:Piperazines / Q000627:therapeutic use; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000627:therapeutic use*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D059767:Recombinational DNA Repair / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics
D001562:Benzimidazoles; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib
DNA repair defects; bladder cancer; polyadenosine diphosphate (ADP) ribose polymerase 1 (PARP1) inhibition; prostate adenocarcinoma; prostate cancer; renal cell carcinoma; targeted therapy; urothelial cell carcinoma