Research ArticleCancer

Targeting tumor phenotypic plasticity and metabolic remodeling in adaptive cross-drug tolerance

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Science Signaling  20 Aug 2019:
Vol. 12, Issue 595, eaas8779
DOI: 10.1126/scisignal.aas8779

Metabolic remodeling for drug resistance

Commonly used chemotherapies can lead to resistance to drugs with different modes of actions. Goldman et al. investigated why breast cancer cells treated with taxanes become resistant to the unrelated, routinely used doxorubicin. The authors found that taxane-treated breast cancer cells became more reliant on oxidative and non-oxidative glucose metabolism. Computational modeling predicted effective targeting of the drug-tolerant cells if a glucose metabolism inhibitor was coadministered with doxorubicin, after the metabolism of cells had been rewired by the initial taxane treatment. This prediction was validated in cultured breast cancer cells, mouse models of breast cancer, and human tumor samples grown in an explant system. These results show not only the potential of metabolic inhibitors in cancer therapy but also the importance of therapy dynamics in achieving successful clinical outcomes (see also the Focus by Paudel and Quaranta).

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