Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer

Jennifer Y Ge; Shaokun Shu; Mijung Kwon; Bojana Jovanović; Katherine Murphy; Anushree Gulvady; Anne Fassl; Anne Trinh; Yanan Kuang; Grace A Heavey; Adrienne Luoma; Cloud Paweletz; Aaron R Thorner; Kai W Wucherpfennig; Jun Qi; Myles Brown; Piotr Sicinski; Thomas O McDonald; David Pellman; Franziska Michor; Kornelia Polyak

doi:10.1038/s41467-020-16170-3

Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer

Nat Commun. 2020 May 11;11(1):2350. doi: 10.1038/s41467-020-16170-3.

Authors

Jennifer Y Ge^{1

2

3}, Shaokun Shu^{1

4

5}, Mijung Kwon^{6

7

8}, Bojana Jovanović^{1

4

9}, Katherine Murphy¹, Anushree Gulvady^{1

4}, Anne Fassl^{10

11}, Anne Trinh^{1

4}, Yanan Kuang¹², Grace A Heavey¹², Adrienne Luoma^{13

14}, Cloud Paweletz¹², Aaron R Thorner^{1

15}, Kai W Wucherpfennig^{13

14

16}, Jun Qi^{4

10}, Myles Brown^{1

4

16

17}, Piotr Sicinski^{10

11}, Thomas O McDonald^{2

18

19

20}, David Pellman^{6

7

16

18

21}, Franziska Michor^{22

23

24

25

26

27}, Kornelia Polyak^{28

29

30

31

32

33}

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
² Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
³ Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA, 02115, USA.
⁴ Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
⁵ Peking University Cancer Hospital and Institute, Beijing, 100142, China.
⁶ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
⁷ Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA.
⁸ Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, 120-750, Korea.
⁹ Eli and Edythe L. Broad Institute, Cambridge, MA, 02142, USA.
¹⁰ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
¹¹ Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
¹² Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
¹³ Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
¹⁴ Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, 02115, USA.
¹⁵ Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
¹⁶ Ludwig Center at Harvard, Harvard Medical School, Boston, MA, 02115, USA.
¹⁷ Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
¹⁸ Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
¹⁹ Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.
²⁰ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA.
²¹ Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.
²² Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. michor@jimmy.harvard.edu.
²³ Eli and Edythe L. Broad Institute, Cambridge, MA, 02142, USA. michor@jimmy.harvard.edu.
²⁴ Ludwig Center at Harvard, Harvard Medical School, Boston, MA, 02115, USA. michor@jimmy.harvard.edu.
²⁵ Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. michor@jimmy.harvard.edu.
²⁶ Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA. michor@jimmy.harvard.edu.
²⁷ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA. michor@jimmy.harvard.edu.
²⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. kornelia_polyak@dfci.harvard.edu.
²⁹ Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA. kornelia_polyak@dfci.harvard.edu.
³⁰ Eli and Edythe L. Broad Institute, Cambridge, MA, 02142, USA. kornelia_polyak@dfci.harvard.edu.
³¹ Ludwig Center at Harvard, Harvard Medical School, Boston, MA, 02115, USA. kornelia_polyak@dfci.harvard.edu.
³² Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. kornelia_polyak@dfci.harvard.edu.
³³ Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. kornelia_polyak@dfci.harvard.edu.

Abstract

BET inhibitors are promising therapeutic agents for the treatment of triple-negative breast cancer (TNBC), but the rapid emergence of resistance necessitates investigation of combination therapies and their effects on tumor evolution. Here, we show that palbociclib, a CDK4/6 inhibitor, and paclitaxel, a microtubule inhibitor, synergize with the BET inhibitor JQ1 in TNBC lines. High-complexity DNA barcoding and mathematical modeling indicate a high rate of de novo acquired resistance to these drugs relative to pre-existing resistance. We demonstrate that the combination of JQ1 and palbociclib induces cell division errors, which can increase the chance of developing aneuploidy. Characterizing acquired resistance to combination treatment at a single cell level shows heterogeneous mechanisms including activation of G1-S and senescence pathways. Our results establish a rationale for further investigation of combined BET and CDK4/6 inhibition in TNBC and suggest novel mechanisms of action for these drugs and new vulnerabilities in cells after emergence of resistance.

Publication types

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

MeSH terms

Animals
Azepines / pharmacology
Cell Cycle Checkpoints / drug effects
Cell Proliferation / drug effects
Clone Cells
Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
Cyclin-Dependent Kinase 4 / metabolism
Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
Cyclin-Dependent Kinase 6 / metabolism
DNA, Neoplasm / metabolism
Drug Resistance, Neoplasm* / drug effects
Drug Synergism
Female
Gene Expression Regulation, Neoplastic / drug effects
Mice
Models, Biological
Mutation / genetics
Paclitaxel / pharmacology
Piperazines / pharmacology
Ploidies
Proteins / antagonists & inhibitors*
Proteins / metabolism
Pyridines / pharmacology
Retinoblastoma Protein / genetics
Retinoblastoma Protein / metabolism
Treatment Outcome
Triazoles / pharmacology
Triple Negative Breast Neoplasms / drug therapy*
Triple Negative Breast Neoplasms / genetics
Up-Regulation / drug effects
Up-Regulation / genetics

Substances

(+)-JQ1 compound
Azepines
DNA, Neoplasm
Piperazines
Proteins
Pyridines
Retinoblastoma Protein
Triazoles
bromodomain and extra-terminal domain protein, human
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6
palbociclib
Paclitaxel

Abstract

Publication types

MeSH terms

Substances

Grants and funding