Abstract
Platinum-based chemotherapy is the cornerstone of ovarian cancer treatment, and its efficacy is dependent on the generation of DNA damage, with subsequent induction of apoptosis. Inappropriate or aberrant activation of the DNA damage response network is associated with resistance to platinum, and defects in DNA repair pathways play critical roles in determining patient response to chemotherapy. In ovarian cancer, tumor cell defects in homologous recombination – a repair pathway activated in response to double-strand DNA breaks (DSB) – are most commonly associated with platinum-sensitive disease. However, despite initial sensitivity, the emergence of resistance is frequent. Here, we review strategies for directly interfering with DNA repair pathways, with particular focus on direct inhibition of non-homologous end joining (NHEJ), another DSB repair pathway. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a core component of NHEJ and it has shown considerable promise as a chemosensitization target in numerous cancer types, including ovarian cancer where it functions to promote platinum-induced survival signaling, via AKT activation. The development of pharmacological inhibitors of DNA-PKcs is on-going, and clinic-ready agents offer real hope to patients with chemoresistant disease.
Highlights
Molecular Therapy Laboratory, Department of Surgery and Cancer, Ovarian Cancer Action Research Centre, Imperial College London, London, UK
Platinum-based chemotherapy is the cornerstone of ovarian cancer treatment, and its efficacy is dependent on the generation of DNA damage, with subsequent induction of apoptosis
Inappropriate or aberrant activation of the DNA damage response network is associated with resistance to platinum, and defects in DNA repair pathways play critical roles in determining patient response to chemotherapy
Summary
Ovarian cancer is the seventh most common cancer amongst women worldwide with an incidence of 6.1 [age-standardized rate (ASR)] per 100,000, and a mortality rate of 3.7 (ASR) [1]. Direct binding to genomic DNA (gDNA) can result in a number of lesions: the initial lesion formed is bulky platinum-DNA adducts that can mediate intra- and inter-strand crosslinks If these are not removed but are encountered by the cells’ transcription or replication machinery, stalling of these processes can lead to the generation of DNA breaks, either single-strand DNA breaks (SSB) or double-strand DNA breaks (DSB). Non-DNA targets of cis- and carboplatin include components of the cell membrane lipid bilayer, such as phospholipids and phosphatidylserine, and cytoplasmic targets such as cytoskeletal microfilaments, thiol-containing peptides, proteins, and RNA [11, 13] These compounds can alter the activity of enzymes, receptors, and other proteins through coordination to sulfur atoms of cysteine and/or methionine residues and to nitrogen atoms of histidine residues [14]. We highlight the non-homologous end joining (NHEJ) pathway as an under-explored target for therapeutic discovery and use DNA-dependent protein kinase catalytic subunit (DNA-PKcs) as an example of how this pathway can be targeted therapeutically (see Figure 1 for graphical summary and Table 1 for a summary of the key messages)
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