Abstract
In sporadic epithelial ovarian cancer (EOC), the inactivation of BRCA1 through various mechanisms is a relatively common event. BRCA1 protein dysfunction results in the breakdown of various critical pathways in the cell, notably, the DNA damage response and repair pathway. Tumors from patients with BRCA1 germline mutations have an increased sensitivity to DNA damaging chemotherapeutic agents, such as cisplatin, due to defective DNA repair. Thus, inhibiting BRCA1 in sporadic EOC using novel targeted therapies is an attractive strategy for the treatment of advanced or recurrent EOC. Several classes of small molecule inhibitors that affect BRCA1 have now been tested in preclinical and clinical studies suggesting that this is a rational therapeutic approach. The aim of this paper is to provide an understanding of how BRCA1 has evolved into a promising target for the treatment of sporadic disease and to outline the main potential small molecule inhibitors of BRCA1 in EOC.
Highlights
Up to 10% of epithelial ovarian cancers (EOCs) are caused by germline mutations in the tumor suppressor genes, Breast Cancer 1 (BRCA1) and BRCA2 [1, 2]
BRCA1 is known to have a role in the ubiquitin-proteasome proteolysis pathway, whereby damaged and misfolded proteins are tagged with a polyubiquitin chain and targeted for ATP-dependent degradation by the 26S proteasome [42]
The array of cellular processes in which BRCA1 plays an integral role offers several mechanisms by which its function could be targeted for the treatment of EOC
Summary
Up to 10% of epithelial ovarian cancers (EOCs) are caused by germline mutations in the tumor suppressor genes, Breast Cancer 1 (BRCA1) and BRCA2 [1, 2]. BRCA1 deficiency is believed to result in deregulation of the carefully coordinated DNA repair cascade and thereby renders tumor cells more vulnerable to DNA damaging agents and genomic instability. While this may appear to be a distinct disadvantage for these cells in terms of tumorigenesis, this situation can be advantageous and potentially exploitable in the context of enhancing the response to DNA damaging chemotherapeutic drugs. A review of BRCA1 gene therapy is provided as well as an overview of the preclinical and clinical studies on the most relevant small molecular inhibitors, poly(ADPribose) polymerase-1 (PARP), histone deacetylases (HDAC), checkpoint kinases (CHKs), and proteasome inhibitors in the context of how these agents alter the BRCA1 pathway to enhance sensitivity to platinum-based chemotherapy. The potential for clinical use of BRCA1 as a biomarker in EOC is reviewed
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