Anticancer drugs' ability to concentrate in condensates containing their targets affected activity.
Major Finding: Anticancer drugs' ability to concentrate in condensates containing their targets affected activity.
Concept: The drugs' physicochemical properties, not their targets' presence, controlled drug partitioning.
Impact: If these findings relate to efficacy in vivo, there are implications for drug design and resistance.
Phase separation of non–membrane bound condensates of specific biomolecules has been observed in cells. Klein, Boija, and colleagues hypothesized that some of the targets of small-molecule anticancer drugs may partition into these condensates and that the efficacy of these drugs may be related to their ability to penetrate the condensates containing their targets. Their investigation revealed that such condensates could be visualized in both normal and tumor tissues and that small-molecule dyes and dextrans could penetrate the condensates. Thus, small-molecule drugs—which are generally similar in size to or smaller than the dyes and dextrans tested—would not be prevented from entering the condensates due to size constraints. In contrast to the dyes and dextrans, multiple small-molecule anticancer drugs tested exhibited selective partitioning into various nuclear condensates, and this effect was independent of whether the drugs' targets existed in the condensates in which they preferentially accumulated. Instead, the physicochemical properties of each drug and the proteins that made up each type of condensate accounted for the differential drug concentrations. Suggesting that variable partitioning of drugs into different types of condensates affected the drugs' activity, experiments using cisplatin showed that DNA platination was greatest in condensates in which cisplatin accumulated. Further investigation involving tamoxifen and its target, estrogen receptor α (ERα), revealed that alterations in condensate biology may be a mechanism mediating drug resistance: Overexpression of a predominant component of ERα-containing condensates doubled the size of the condensates and diluted the tamoxifen within them. Collectively, this work suggests that the ability of drugs to reach therapeutically relevant concentrations inside condensates containing their targets may play a role in their efficacy and has potential implications for understanding drug resistance and improving drug design.
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