Fueling resistance

A recent study (Cancer Cell 23, 811–825) has uncovered a metabolic adaptation that promotes the growth of therapy-resistant tumor cells and that may also be a targetable vulnerability.

The study broadly characterizes the resistance to chemotherapy of a previously described subpopulation of melanoma cells. This subset of cells within the tumors, which are known to express high levels of the epigenetic modulator JARID1B and to proliferate more slowly than the bulk of the tumor, are enriched after therapeutic regimes that target rapid-growing cells. Alexander Roesch et al. now show that this melanoma subset can also thrive under treatment with other anticancer drugs.

The authors surveyed the resistant cell population for potential therapeutic targets in the hope of identifying strategies to fully eradicate tumors and prevent recurrence. They found that, compared with melanoma cells with low expression or knockdown of JARID1B, JARID1B^high melanoma cells had an increase in mitochondrial components that corresponded with increased oxygen consumption, suggesting that JARID1B^high cells undergo a metabolic adaptation that may support their growth as well as drug resistance properties.

The researchers then showed that inhibition of the mitochondrial respiratory chain in the resistant population induced cell death. In addition, combining targeting of the mitochondrial respiratory chain with chemotherapy could sensitize the drug's cytotoxic effect in some of the melanoma cell lines studied and reduce tumor growth in vivo.

The results support that there is intimate coupling between a tumor cell's proliferative and metabolic states and suggest that compounds that target mitochondrial function currently used in diabetic patients could prevent the development of resistance to cancer therapies.