Editors' ChoiceCancer

Synthetic lethality and beyond

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Science Translational Medicine  16 Nov 2016:
Vol. 8, Issue 365, pp. 365ec182
DOI: 10.1126/scitranslmed.aal0070

Normal and cancer cells rely on DNA damage repair to survive. In tumor cells with DNA breaks and defective homologous recombination, such as those with mutations in the BRCA gene, DNA repair is maintained through base excision repair, mediated in part by poly (ADP-ribose) polymerase (PARP). The use of PARP inhibitors (PARPi) in this setting results in a breakdown of both pathways and cell death through a mechanism known as synthetic lethality. This has been the rationale for the clinical development of PARPi for cancer patients with germline or somatic BRCA alterations.

PARP1 interacts noncovalently with the DNA methyltransferase DNMT1, and a PARP1-DNMT1 containing complex is recruited to sites of DNA damage. Muvarak et al. found that combining PARPi drugs, which trap the PARP1 at sites of DNA damage, with DNA methyltransferase (DNMT) inhibitors, which incorporate into replicating DNA and covalently bind DMNTs, enhances the strength and duration of PARP1 binding to chromatin and thereby increases the efficacy of PARPi in cancer cells. The combination of low doses of PARPi plus DNMT inhibitors was synergistic in models of triple negative breast cancer and acute myelogenous leukemia. Importantly, the benefit was observed regardless of BRCA mutation status, suggesting that a broader group of patients may benefit from the combination.

This study supports an interplay between DNA repair and epigenetic machineries in cancer. Whether this interaction and therapeutic benefit is solely due to the PARP1-DNMT1 complex and PARP1 trapping and/or potentially mediated through other effects—such as changes in methylation and epigenetic regulation of gene expression, genomic instability, or other cofactors—and whether this is also relevant to other cancer subtypes, remain to be explored.

N. E. Muvarak et al., Enhancing the cytotoxic effects of PARP inhibitors with DNA demethylating agents – A potential therapy for cancer. Cancer Cell 30, 637–650 (2016). [Abstract]

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