Abstract
Simple SummaryOvarian cancer is the most lethal gynecologic malignancy and is characterized by genomic instability and DNA repair defects. PARP inhibitors (PARPi) changed the treatment paradigm of ovarian cancer but the development of resistance to PARPi is a pressing clinical challenge. In this review, we discuss how RecQ helicases can be targeted as a novel therapeutic strategy to prevent such treatment resistance. The combination of helicase inhibitor with a PARP inhibitor (PARPi) or ATR inhibitor may overcome PARPi resistance in ovarian cancer.RecQ helicases are essential for DNA replication, recombination, DNA damage repair, and other nucleic acid metabolic pathways required for normal cell growth, survival, and genome stability. More recently, RecQ helicases have been shown to be important for replication fork stabilization, one of the major mechanisms of PARP inhibitor resistance. Cancer cells often have upregulated helicases and depend on these enzymes to repair rapid growth-promoted DNA lesions. Several studies are now evaluating the use of RecQ helicases as potential biomarkers of breast and gynecologic cancers. Furthermore, RecQ helicases have attracted interest as possible targets for cancer treatment. In this review, we discuss the characteristics of RecQ helicases and their interacting partners that may be utilized for effective treatment strategies (as cancers depend on helicases for survival). We also discuss how targeting helicase in combination with DNA repair inhibitors (i.e., PARP and ATR inhibitors) can be used as novel approaches for cancer treatment to increase sensitivity to current treatment to prevent rise of treatment resistance.
Highlights
Since the discovery of helicases in 1976, there has been immense progress in their classification, characterization, and our understanding of their functions [1–3]
There are contradictory reports suggesting the roles of BLM as tumor suppressor versus oncogenic driver, it is likely that proper BLM expression is required for genome stability and any disruption to that balance could lead to tumorigenesis
Since RecQ helicases are involved in unwinding DNA to promote the replication fork restart and HR repair, combining PARP inhibitors (PARPis) with helicase inhibition might be a viable option to enhance the efficacy of PARPi
Summary
Since the discovery of helicases in 1976, there has been immense progress in their classification, characterization, and our understanding of their functions [1–3]. Helicases are molecular motors that can separate DNA or RNA double helices using the energy generated from ATP hydrolysis [4] This function makes helicases critical players in cellular replication, transcription, DNA repair, and the maintenance of both genomic integrity and cellular homeostasis. There are contradictory reports suggesting the roles of BLM as tumor suppressor versus oncogenic driver, it is likely that proper BLM expression (no higher or lower expression) is required for genome stability and any disruption to that balance could lead to tumorigenesis. This may explain why patients with Bloom’s syndrome with genomic instability have a higher risk of developing cancer. More studies need to be conducted to test the potential use of BLM as a druggable target or biomarker for cancer therapy (Table 1)
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