Research ArticleCancer

Systematic identification of signaling pathways with potential to confer anticancer drug resistance

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Science Signaling  23 Dec 2014:
Vol. 7, Issue 357, pp. ra121
DOI: 10.1126/scisignal.aaa1877

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Finding New Targets for Drug-Resistant Cancers

The development of drug resistance is a common problem in cancer patients. Knowing how drug resistance emerged in a tumor can inform clinical strategy. Martz et al. devised a drug screen to identify pathways of resistance when cancer cells were treated with drugs that are used in the clinic. Along with pathways known to mediate drug resistance, such as the MAPK and PI3K pathways, activation of the Notch1 pathway caused drug resistance in various types of cancer cells in culture. Inhibiting Notch1 signaling restored drug efficacy in cells in culture and in xenografts in mice. Intriguingly, Notch signaling mediated drug resistance to an estrogen receptor–targeted therapy used in breast cancer and to a kinase-targeted therapy used in melanoma, suggesting that this single pathway may be important in multiple types of drug-resistant cancers. Indeed, tumors of some patients with relapsed breast cancer or melanoma had increased markers of Notch1 signaling. In the Research Article by Winter et al. also in this issue, this screening method identified a pathway of drug resistance in bone marrow cancer. More generally, by screening entire signaling pathways instead of individual genes, the work of Martz et al. shows how we can quickly map pathways to the diverse properties of cancer cells.

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