Molecular Pathways: Targeting PARP in Cancer Treatment
- 1 March 2013
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 19 (5), 977-984
- https://doi.org/10.1158/1078-0432.ccr-12-0163
Abstract
Poly (ADP-ribose) polymerases (PARP) are a family of nuclear protein enzymes involved in the DNA damage response. The role of PARP-1 in base excisional repair has been extensively characterized. More recent in vitro studies additionally implicate a role for PARP-1 in facilitating homologous recombination and nonhomologous end-joining. The more faithful process of homologous recombination repair of double-stranded DNA breaks involves localization of BRCA-1 and BRCA-2 to sites of DNA damage, resection of the double-stranded break, and gap-filling DNA synthesis using the homologous sister chromatid as a template. Simultaneous dysfunction of both DNA repair pathways decreases the ability of cells to compensate, and forms the basis for the concept of synthetic lethality. Treatment strategies, thus far, have focused on two main principles: (i) exploitation of the concept of synthetic lethality in homologous recombination–deficient tumors, primarily in breast and ovarian cancer patients with BRCA mutation, and (ii) as radiosensitizers and chemosensitizers. BRCA deficiency accounts for only a fraction of dysfunction in homologous recombination repair. Epigenetic alterations of BRCA function and defects within the Fanconi anemia pathway also result in defective DNA repair. Rational therapeutic combinations exploiting alternate mechanisms of defective DNA repair, abrogation of cell-cycle checkpoints, and additional functions of PARP-1 present novel opportunities for further clinical development of PARP inhibitors. On the basis of the results of clinical studies of PARP inhibitors thus far, it is imperative that future development of PARP inhibitors take a more refined approach, identifying the unique subset of patients that would most benefit from these agents, determining the optimal time for use, and identifying the optimal combination partner in any particular setting. Clin Cancer Res; 19(5); 977–84. ©2012 AACR.Keywords
This publication has 60 references indexed in Scilit:
- The poly(ADP-Ribose) polymerase inhibitor ABT-888 reduces radiation-induced nuclear EGFR and augments head and neck tumor response to radiotherapyRadiotherapy and Oncology, 2011
- NF-κB mediates radio-sensitization by the PARP-1 inhibitor, AG-014699Oncogene, 2011
- Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibitionNature Medicine, 2011
- NF-kappa B addiction and its role in cancer: 'one size does not fit all'Oncogene, 2011
- A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumoursBritish Journal of Cancer, 2011
- Iniparib plus Chemotherapy in Metastatic Triple-Negative Breast CancerNew England Journal of Medicine, 2011
- PARP inhibition: PARP1 and beyondNature Reviews Cancer, 2010
- Preclinical Modeling of a Phase 0 Clinical Trial: Qualification of a Pharmacodynamic Assay of Poly (ADP-Ribose) Polymerase in Tumor Biopsies of Mouse XenograftsClinical Cancer Research, 2008
- Pharmacological inhibition of poly(ADP-ribose) polymerase inhibits angiogenesisBiochemical and Biophysical Research Communications, 2006
- PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathwaysNucleic Acids Research, 2006