Editors' ChoiceCancer

Harnessing cellular stress to kill myeloma

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Sci. Signal.  15 Sep 2015:
Vol. 8, Issue 394, pp. ec262
DOI: 10.1126/scisignal.aad4158

Cancer cells frequently experience oxidative stress (a consequence of an imbalance in redox state) and replication stress (a consequence of stalled replication forks), both of which can cause DNA damage. Cancer cells cope with this increased cellular stress through various antioxidant and DNA repair pathways. The kinase ATR promotes DNA repair. Cottini et al. found that multiple myeloma cells are particularly sensitive to inhibition of ATR when also experiencing oxidative stress. In multiple myeloma cell lines, the expression of cell cycle regulatory genes positively correlated with the abundance of DNA damage and replication stress markers; in patients with aggressive multiple myeloma, these gene signatures correlated with the expression of the gene encoding the transcription factor MYC and of genes associated with reactive oxygen species (ROS) metabolism. By manipulating the abundance of MYC, the authors found that MYC induced both replication stress and DNA repair, as well as ROS production and increased antioxidant enzyme abundance. Thus, MYC induced both the stress and the adaptive response to the stress. Knocking down or chemically inhibiting ATR impaired DNA damage repair and induced apoptosis in multiple myeloma cell lines. Cells overexpressing MYC were more sensitive to ATR inhibition than were either parental or MYC-silenced cells. Adding the antioxidant NAC to cultured myeloma cells stimulated proliferation in MYC-overexpressing cells, whereas enhancing ROS production by adding piperlongumine increased the abundance of DNA damage markers and triggered apoptosis in MYC-overexpressing cells. Cell death was enhanced selectively in MYC-overexpressing cells by combining piperlongumine with ATR inhibition. The findings suggest that increasing oxidative stress and blocking the cells’ ability to repair the resulting DNA damage may be an effective therapeutic strategy in patients with MYC-driven multiple myeloma.

F. Cottini, T. Hideshima, R. Suzuki, Y.-T. Tai, G. Bianchini, P. G. Richardson, K. C. Anderson, G. Tonon, Synthetic lethal approaches exploiting DNA damage in aggressive myeloma. Cancer Discov. 5, 972–987 (2015). [PubMed]