Partitioning of cancer therapeutics in nuclear condensates

Isaac A Klein; Ann Boija; Lena K Afeyan; Susana Wilson Hawken; Mengyang Fan; Alessandra Dall'Agnese; Ozgur Oksuz; Jonathan E Henninger; Krishna Shrinivas; Benjamin R Sabari; Ido Sagi; Victoria E Clark; Jesse M Platt; Mrityunjoy Kar; Patrick M McCall; Alicia V Zamudio; John C Manteiga; Eliot L Coffey; Charles H Li; Nancy M Hannett; Yang Eric Guo; Tim-Michael Decker; Tong Ihn Lee; Tinghu Zhang; Jing-Ke Weng; Dylan J Taatjes; Arup Chakraborty; Phillip A Sharp; Young Tae Chang; Anthony A Hyman; Nathanael S Gray; Richard A Young

doi:10.1126/science.aaz4427

Partitioning of cancer therapeutics in nuclear condensates

Science. 2020 Jun 19;368(6497):1386-1392. doi: 10.1126/science.aaz4427.

Authors

Isaac A Klein^#^{1

2}, Ann Boija^#¹, Lena K Afeyan^{1

3}, Susana Wilson Hawken^{1

3}, Mengyang Fan^{4

5}, Alessandra Dall'Agnese¹, Ozgur Oksuz¹, Jonathan E Henninger¹, Krishna Shrinivas^{6

7}, Benjamin R Sabari¹, Ido Sagi¹, Victoria E Clark^{1

8}, Jesse M Platt^{1

9}, Mrityunjoy Kar¹⁰, 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 Hannett¹, Yang Eric Guo¹, Tim-Michael Decker¹³, Tong Ihn Lee¹, Tinghu Zhang^{4

5}, Jing-Ke Weng^{1

3}, Dylan J Taatjes¹³, Arup Chakraborty^{6

7

14

15

16

17

18}, Phillip A Sharp^{3

18}, Young Tae Chang¹⁹, Anthony A Hyman^{11

20}, Nathanael S Gray^{4

5}, Richard A Young²¹

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Cell Nucleus / metabolism*
Chromobox Protein Homolog 5
Chromosomal Proteins, Non-Histone / genetics
Chromosomal Proteins, Non-Histone / metabolism
Drug Resistance, Neoplasm*
Green Fluorescent Proteins / genetics
Green Fluorescent Proteins / metabolism
Humans
Mediator Complex Subunit 1 / genetics
Mediator Complex Subunit 1 / metabolism
Neoplasms / drug therapy*
Neoplasms / metabolism*
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Nucleophosmin
Recombinant Proteins / genetics
Recombinant Proteins / metabolism
Serine-Arginine Splicing Factors / genetics
Serine-Arginine Splicing Factors / metabolism
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

Antineoplastic Agents
BRD4 protein, human
Cell Cycle Proteins
Chromosomal Proteins, Non-Histone
MED1 protein, human
Mediator Complex Subunit 1
Nuclear Proteins
Recombinant Proteins
Transcription Factors
Chromobox Protein Homolog 5
Nucleophosmin
SRSF2 protein, human
Green Fluorescent Proteins
Serine-Arginine Splicing Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding