The maintenance of a pristine genome, free from errors, is necessary to prevent cellular transformation and degeneration. When errors in DNA are detected, DNA damage response (DDR) genes and their regulators are activated to effect repair. When these DDR pathways are themselves mutated or aberrantly downregulated, cancer and neurodegenerative disorders can ensue. Multiple lines of evidence now indicate however that defects in key regulators of DNA repair pathways are highly enriched in human metastasis specimens and hence may be a key step in the acquisition of metastasis and the ability of localized disease to disseminate. Some of the key regulators of checkpoints in the DNA damage response are the TP53 protein and the PARP enzyme family and targeting of these pathways, especially through PARP inhibition, are now being exploited therapeutically to effect significant clinical responses in subsets of individuals particularly in ovarian and prostate cancer, including those with a marked metastatic burden. Targeting DNA repair deficient tumors with drugs that take advantage of the fundamental differences between normal repair proficient cells and repair deficient tumors offers new avenues for treating advanced disease in the future.
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Clinical cancer research : an official journal of the American Association for Cancer Research. 2016 May 11 [Epub ahead of print]
Niall M Corcoran, Michael J Clarkson, Ryan Stuchbery, Christopher M Hovens
Urology and Surgery, Royal Melbourne Hospital, University of Melbourne., Departments of Urology and Surgery, Royal Melbourne Hospital and the University of Melbourne., Division of Urology, Royal Melbourne Hospital and the University of Melbourne., Urology and Surgery, Royal Melbourne Hospital, University of Melbourne .