Editors' ChoiceCancer

Epigenetics make transient states of cancer therapy resistance permanent

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Science Translational Medicine  28 Jun 2017:
Vol. 9, Issue 396, eaan6729
DOI: 10.1126/scitranslmed.aan6729

Abstract

Resistance to targeted cancer therapies is mediated by stabilization of transient insensitive states.

The inevitable development of resistance to most targeted therapies represents a major clinical challenge and impedes the use of these newly developed, less toxic agents for cancer eradication, especially in solid tumors. Competing theories about the mechanisms that drive chemoresistance have demonstrated that resistance can arise via multiple paths and that cancers can be superbly adaptable and unpredictable. Entering the fray, Shaffer et al. used single-cell gene expression profiling to uncover the existence of rare, transient, and nonheritable transcriptional states that confer patient-derived BRAFV600E melanoma cells with resistance to the BRAF inhibitor vemurafenib. Upon treatment with this agent in vitro, most cells undergo apoptosis but some transiently resistant cells survive and continue to proliferate, while their advantageous transcriptional profile is permanently “burned in” via epigenetic reprogramming, supporting long-term resistance. They further identify “jackpot” cells that coexpress multiple resistance-conferring genes, gaining even more of an advantage when challenged with the drug.

The transcriptional profiles of the reprogrammed cells indicated that they were undergoing a process of dedifferentiation and subsequent activation of alternate pro-growth signaling pathways, such as EGFR. This suggests that the cells may now be sensitive to agents targeting the alternate pathways. Importantly, if cancers evolved in a predicable manner, the second targeted agent can be used prior to the stable establishment of the resistant clones, potentially blocking tumor recurrence altogether. However, as we often see, cancer is not as predictable as we would like.

Interestingly, the authors found that these transient states of highly variable gene expression weren’t unique to melanomas, nor were they unique to cancer cells; melanocytes, profiled at the single-cell level, exhibited similar high rates of variability in rare cells. This is important because it suggests that gene expression is perhaps not as stable as one would assume in normal cells, but this conclusion requires additional validation in other cell types.

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