Partitioning of cancer therapeutics in nuclear condensates.

TitlePartitioning of cancer therapeutics in nuclear condensates.
Publication TypeJournal Article
Year of Publication2020
AuthorsKlein IA, Boija A, Afeyan LK, Hawken SWilson, Fan M, Dall'Agnese A, Oksuz O, Henninger JE, Shrinivas K, Sabari BR, Sagi I, Clark VE, Platt JM, Kar M, McCall PM, Zamudio AV, Manteiga JC, Coffey EL, Li CH, Hannett NM, Guo YEric, Decker T-M, Lee TIhn, Zhang T, Weng J-K, Taatjes DJ, Chakraborty A, Sharp PA, Chang YTae, Hyman AA, Gray NS, Young RA
JournalScience
Volume368
Issue6497
Pagination1386-1392
Date Published2020 Jun 19
ISSN1095-9203
KeywordsAntineoplastic Agents, Bromodomain Containing Proteins, Cell Cycle Proteins, Cell Nucleus, Chromobox Protein Homolog 5, Chromosomal Proteins, Non-Histone, Drug Resistance, Neoplasm, Green Fluorescent Proteins, Humans, Mediator Complex Subunit 1, Neoplasms, Nuclear Proteins, Nucleophosmin, Recombinant Proteins, Serine-Arginine Splicing Factors, Transcription Factors
Abstract

The nucleus contains diverse phase-separated condensates that compartmentalize and concentrate biomolecules with distinct physicochemical properties. Here, we investigated whether condensates concentrate small-molecule cancer therapeutics such that their pharmacodynamic properties are altered. We found that antineoplastic drugs become concentrated in specific protein condensates in vitro and that this occurs through physicochemical properties independent of the drug target. This behavior was also observed in tumor cells, where drug partitioning influenced drug activity. Altering the properties of the condensate was found to affect the concentration and activity of drugs. These results suggest that selective partitioning and concentration of small molecules within condensates contributes to drug pharmacodynamics and that further understanding of this phenomenon may facilitate advances in disease therapy.

DOI10.1126/science.aaz4427
Alternate JournalScience
PubMed ID32554597
PubMed Central IDPMC7735713
Grant ListR01 GM123511 / GM / NIGMS NIH HHS / United States
R01 GM117370 / GM / NIGMS NIH HHS / United States
T32 GM007287 / GM / NIGMS NIH HHS / United States
T32 DK007191 / DK / NIDDK NIH HHS / United States
P01 CA155258 / CA / NCI NIH HHS / United States
T32 GM087237 / GM / NIGMS NIH HHS / United States
R01 GM034277 / GM / NIGMS NIH HHS / United States
U01 CA213333 / CA / NCI NIH HHS / United States
R01 HG002668 / HG / NHGRI NIH HHS / United States