Defining and targeting wild-type BRCA high-grade serous ovarian cancer: DNA repair and cell cycle checkpoints

ABSTRACT

Introduction: Molecular analyzes including molecular descriptor/phenotype interactions have led to better characterization of epithelial ovarian cancer patients, including a definition of a BRCA wild-type (BRCAwt) phenotype. Understanding how and when to use agents targeted against dependent BRCAwt pathways or other molecular events at disease progression is an important translational and therapeutic direction in ovarian cancer research.

Areas covered: In this overview, we provide definitions and descriptions of a BRCAwt genotype and phenotype. We discuss novel investigational drugs that hold promise for the treatment of BRCAwt ovarian cancer, including inhibitors of poly(ADP-ribose) polymerase, ribonucleotide reductase, DNA protein kinase-catalytic subunit, ataxia-telangiectasia-mutated kinase (ATM), ataxia-telangiectasia mutated and Rad3-related kinase (ATR), CHK 1/2, cyclin kinases, glutaminase-1, WEE1 kinase, as well as tumor microenvironment and angiogenesis inhibitors. This article explores the known and the emerging areas of clinical research on patients with BRCAwt ovarian cancer.

Expert opinion: Discovery of molecular changes tied to annotated disease information, along with an expanding array of pathway targets and targeted therapeutic agents, creates optimism and opportunity for women with ovarian cancer. Using precision oncology approaches, clinical researchers are, and will be, poised to select more effective treatments for ovarian cancer patients.

KEYWORDS:

• Homologous recombination
• DNA repair deficiencies
• BRCA wild type
• BRCAwt
• high grade serous ovarian cancer
• biomarkers
• PARP
• DNA-PKcs
• ATM
• ATR
• CHK1
• CHK2
• DNA damage repair
• cell cycle
• immune checkpoint inhibitors

Article Highlights

• BRCA1- or BRCA2-wild type HGSOC will benefit initially from platinum-based therapies and PARP inhibition, although resistance and progressive disease occur earlier and more often than in gBRCA HGSOC.

• No other clear molecular drivers have been identified to guide precision treatment for women with BRCA wild-type ovarian cancers.

• Genomic instability is the hallmark of all HGSOC leading to use of agents dysregulating DNA repair and/or promoting DNA damage, targeting cell cycle, or in combinations with tissue microenvironment modifiers.

• Translational correlative studies need to be included in all trials to advance our understanding of the disease, treatment response or lack thereof, and molecular descriptor/phenotype interactions.

• The greatest impediment against advancing treatments for BRCAwt ovarian cancer is the enrollment of women into clinical trials.

• Molecular characterization of ovarian cancer across the disease spectrum remains critical to personalized treatment selection.

• Identifying pathway targets that convey resistance to modern treatment remains central to the meeting of therapeutic needs of women with ovarian cancer.

This box summarizes key points contained in the article.

Acknowledgments

The authors acknowledge the outstanding assistance of Nichola Cruikshanks, PhD and Timothy Schulz, PhD for technical assistance and proof editing for this manuscript.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Peer Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.