The emerging role of homologous recombination repair and PARP inhibitors in genitourinary malignancies

Kalen J. Rimar, Phuoc T. Tran, Richard S. Matulewicz, Maha Hussain, Joshua J. Meeks*

*Corresponding author for this work

Research output: Contribution to journalReview article

12 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1912-1924
Number of pages13
JournalCancer
Volume123
Issue number11
DOIs
StatePublished - Jun 1 2017

Fingerprint

Recombinational DNA Repair
DNA Repair
Urogenital Neoplasms
Homologous Recombination
Neoplasms
DNA Damage
Prostatic Neoplasms
Poly Adenosine Diphosphate Ribose
Poly(ADP-ribose) Polymerases
Urinary Bladder Neoplasms
Genes
Cell Death
Poly(ADP-ribose) Polymerase Inhibitors
Clinical Trials
Mutation
Enzymes
Therapeutics

Keywords

  • 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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Rimar, Kalen J. ; Tran, Phuoc T. ; Matulewicz, Richard S. ; Hussain, Maha ; Meeks, Joshua J. / The emerging role of homologous recombination repair and PARP inhibitors in genitourinary malignancies. In: Cancer. 2017 ; Vol. 123, No. 11. pp. 1912-1924.
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The emerging role of homologous recombination repair and PARP inhibitors in genitourinary malignancies. / Rimar, Kalen J.; Tran, Phuoc T.; Matulewicz, Richard S.; Hussain, Maha; Meeks, Joshua J.

In: Cancer, Vol. 123, No. 11, 01.06.2017, p. 1912-1924.

Research output: Contribution to journalReview article

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T1 - The emerging role of homologous recombination repair and PARP inhibitors in genitourinary malignancies

AU - Rimar, Kalen J.

AU - Tran, Phuoc T.

AU - Matulewicz, Richard S.

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AU - Meeks, Joshua J.

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AB - 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.

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