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

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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).

Abstract

Metastable phenotypic state transitions in cancer cells can lead to the development of transient adaptive resistance or tolerance to chemotherapy. Here, we report that the acquisition of a phenotype marked by increased abundance of CD44 (CD44Hi) by breast cancer cells as a tolerance response to routinely used cytotoxic drugs, such as taxanes, activated a metabolic switch that conferred tolerance against unrelated standard-of-care chemotherapeutic agents, such as anthracyclines. We characterized the sequence of molecular events that connected the induced CD44Hi phenotype to increased activity of both the glycolytic and oxidative pathways and glucose flux through the pentose phosphate pathway (PPP). When given in a specific order, a combination of taxanes, anthracyclines, and inhibitors of glucose-6-phosphate dehydrogenase (G6PD), an enzyme involved in glucose metabolism, improved survival in mouse models of breast cancer. The same sequence of the three-drug combination reduced the viability of patient breast tumor samples in an explant system. Our findings highlight a convergence between phenotypic and metabolic state transitions that confers a survival advantage to cancer cells against clinically used drug combinations. Pharmacologically targeting this convergence could overcome cross-drug tolerance and could emerge as a new paradigm in the treatment of cancer.

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