Preventing Damage Limitation: Targeting DNA-PKcs and DNA Double-Strand Break Repair Pathways for Ovarian Cancer Therapy

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.

Keywords: DNA repair; DNA-PKcs; chemosensitization; ovarian cancer; platinum resistance.

Figure 1

Graphical summary: DNA repair proteins such as DNA-PKcs can be targeted to improve outcomes for patients with ovarian cancer. Ovarian cancers with defects in the homologous recombination (HR) pathway are initially sensitive to platinum treatment, and also respond to Olaparib that targets the base excision repair pathway protein PARP. For the majority of cases, which are HR proficient, platinum-based chemotherapy is still utilized but resistance is likely. For patients with platinum-resistant disease, inhibition of DNA-PKcs, a key component of the non-homologous end joining pathway, represents a targeted approach to prevent the pro-survival AKT and anti-apoptotic signaling associated with resistance.