2. Academic Validation
  3. Partitioning of cancer therapeutics in nuclear condensates

Partitioning of cancer therapeutics in nuclear condensates

  • Science. 2020 Jun 19;368(6497):1386-1392. doi: 10.1126/science.aaz4427.
Isaac A Klein # 1 2,  Ann Boija # 1,  Lena K Afeyan 1 3,  Susana Wilson Hawken 1 3,  Mengyang Fan 4 5,  Alessandra Dall'Agnese 1,  Ozgur Oksuz 1,  Jonathan E Henninger 1,  Krishna Shrinivas 6 7,  Benjamin R Sabari 1,  Ido Sagi 1,  Victoria E Clark 1 8,  Jesse M Platt 1 9,  Mrityunjoy Kar 10,  Patrick M McCall 10 11 12,  Alicia V Zamudio 1 3,  John C Manteiga 1 3,  Eliot L Coffey 1 3,  Charles H Li 1 3,  Nancy M Hannett 1,  Yang Eric Guo 1,  Tim-Michael Decker 13,  Tong Ihn Lee 1,  Tinghu Zhang 4 5,  Jing-Ke Weng 1 3,  Dylan J Taatjes 13,  Arup Chakraborty 6 7 14 15 16 17 18,  Phillip A Sharp 3 18,  Young Tae Chang 19,  Anthony A Hyman 11 20,  Nathanael S Gray 4 5,  Richard A Young 21
Affiliations

Affiliations

  • 1 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • 2 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • 3 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 4 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 5 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • 6 Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 7 Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 8 Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • 9 Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
  • 10 Max Planck Institute for the Physics of Complex Systems, 01187 Dresden, Germany.
  • 11 Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
  • 12 Center for Systems Biology Dresden, 01307 Dresden, Germany.
  • 13 Department of Biochemistry, University of Colorado, Boulder, CO 80303, USA.
  • 14 Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 15 Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 16 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 17 Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard Medical School, Cambridge, MA 02139, USA.
  • 18 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 19 Department of Chemistry, Pohang University of Science and Technology, and Center for Self-assembly and Complexity, Institute for Basic Science (IBS), Pohang 37673, Republic of Korea.
  • 20 Cluster of Excellence Physics of Life, Technical University of Dresden, 01062 Dresden, Germany.
  • 21 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. [email protected].
  • # Contributed equally.
PMID: 32554597 DOI: 10.1126/science.aaz4427
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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