Partitioning of cancer therapeutics in nuclear condensates

Isaac A. Klein(Harvard University), Ann Boija(Whitehead Institute for Biomedical Research), Lena K. Afeyan(Whitehead Institute for Biomedical Research), Susana Wilson Hawken(Whitehead Institute for Biomedical Research), Mengyang Fan(Harvard University), Alessandra Dall’Agnese(Whitehead Institute for Biomedical Research), Ozgur Oksuz(Whitehead Institute for Biomedical Research), Jonathan E. Henninger(Whitehead Institute for Biomedical Research), Krishna Shrinivas(Massachusetts Institute of Technology), Benjamin R. Sabari(Whitehead Institute for Biomedical Research), Ido Sagi(Whitehead Institute for Biomedical Research), Victoria Clark(Harvard University), Jesse M. Platt(Massachusetts General Hospital), Mrityunjoy Kar(Max Planck Institute for the Physics of Complex Systems), Patrick M. McCall(Max Planck Institute for the Physics of Complex Systems), Alicia V. Zamudio(Whitehead Institute for Biomedical Research), John C. Manteiga(Whitehead Institute for Biomedical Research), Eliot L. Coffey(Whitehead Institute for Biomedical Research), Charles H. Li(Whitehead Institute for Biomedical Research), Nancy M. Hannett(Whitehead Institute for Biomedical Research), Yang Guo(Whitehead Institute for Biomedical Research), Tim-Michael Decker(University of Colorado Boulder), Tong Ihn Lee(Whitehead Institute for Biomedical Research), Tinghu Zhang(Harvard University), Jing‐Ke Weng(Whitehead Institute for Biomedical Research), Dylan J. Taatjes(University of Colorado Boulder), Arup K. Chakraborty(Ragon Institute of MGH, MIT and Harvard), Phillip A. Sharp(Massachusetts Institute of Technology), Young‐Tae Chang(Institute for Basic Science), Anthony A. Hyman(Max Planck Institute of Molecular Cell Biology and Genetics), Nathanael S. Gray(Harvard University), Richard A. Young(Whitehead Institute for Biomedical Research)
Science
June 18, 2020
10.1126/science.aaz4427
Cited by 519Open Access
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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.

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