Pharmacologic Induction of BRCAness in -Proficient Cancers: Expanding PARP Inhibitor Use.
MetadataShow full item record
AbstractThe poly(ADP-ribose) polymerase (PARP) family of proteins has been implicated in numerous cellular processes, including DNA repair, translation, transcription, telomere maintenance, and chromatin remodeling. Best characterized is PARP1, which plays a central role in the repair of single strand DNA damage, thus prompting the development of small molecule PARP inhibitors (PARPi) with the intent of potentiating the genotoxic effects of DNA damaging agents such as chemo- and radiotherapy. However, preclinical studies rapidly uncovered tumor-specific cytotoxicity of PARPi in a subset of cancers carrying mutations in the BReast CAncer 1 and 2 genes (BRCA1/2), which are defective in the homologous recombination (HR) DNA repair pathway, and several PARPi are now FDA-approved for single agent treatment in BRCA-mutated tumors. This phenomenon, termed synthetic lethality, has now been demonstrated in tumors harboring a number of repair gene mutations that produce a BRCA-like impairment of HR (also known as a 'BRCAness' phenotype). However, BRCA mutations or BRCAness is present in only a small subset of cancers, limiting PARPi therapeutic utility. Fortunately, it is now increasingly recognized that many small molecule agents, targeting a variety of molecular pathways, can induce therapeutic BRCAness as a downstream effect of activity. This review will discuss the potential for targeting a broad range of molecular pathways to therapeutically induce BRCAness and PARPi synthetic lethality.
cell cycle inhibitor
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/19122
- Use of poly ADP-ribose polymerase [PARP] inhibitors in cancer cells bearing DDR defects: the rationale for their inclusion in the clinic.
- Authors: Cerrato A, Morra F, Celetti A
- Issue date: 2016 Nov 24
- Dual disruption of DNA repair and telomere maintenance for the treatment of head and neck cancer.
- Authors: Lajud SA, Nagda DA, Yamashita T, Zheng J, Tanaka N, Abuzeid WM, Civantos A, Bezpalko O, O'Malley BW Jr, Li D
- Issue date: 2014 Dec 15
- Role of BRCA Mutations in Cancer Treatment with Poly(ADP-ribose) Polymerase (PARP) Inhibitors.
- Authors: Faraoni I, Graziani G
- Issue date: 2018 Dec 4
- New Targeted Agents in Gynecologic Cancers: Synthetic Lethality, Homologous Recombination Deficiency, and PARP Inhibitors.
- Authors: Liu FW, Tewari KS
- Issue date: 2016 Mar
- Defining and Modulating 'BRCAness'.
- Authors: Byrum AK, Vindigni A, Mosammaparast N
- Issue date: 2019 Sep