Differentiation-state plasticity is a targetable resistance mechanism in basal-like breast cancer

Tyler Risom, Ellen M. Langer, Margaret P. Chapman, Juha Rantala, Andrew J. Fields, Christopher Boniface, Mariano J. Alvarez, Nicholas D. Kendsersky, Carl R. Pelz, Katherine Johnson-Camacho, Lacey E. Dobrolecki, Kwang-Yung Chin, Anil J. Aswani, Nicholas J. Wang, Andrea Califano, Michael T. Lewis, Claire J. Tomlin, Paul Spellman, Andrew Adey, Joe Gray & 1 others Rosalie Sears

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Intratumoral heterogeneity in cancers arises from genomic instability and epigenomic plasticity and is associated with resistance to cytotoxic and targeted therapies. We show here that cell-state heterogeneity, defined by differentiation-state marker expression, is high in triple-negative and basal-like breast cancer subtypes, and that drug tolerant persister (DTP) cell populations with altered marker expression emerge during treatment with a wide range of pathway-targeted therapeutic compounds. We show that MEK and PI3K/mTOR inhibitor-driven DTP states arise through distinct cell-state transitions rather than by Darwinian selection of preexisting subpopulations, and that these transitions involve dynamic remodeling of open chromatin architecture. Increased activity of many chromatin modifier enzymes, including BRD4, is observed in DTP cells. Co-treatment with the PI3K/mTOR inhibitor BEZ235 and the BET inhibitor JQ1 prevents changes to the open chromatin architecture, inhibits the acquisition of a DTP state, and results in robust cell death in vitro and xenograft regression in vivo.

Original languageEnglish (US)
Article number3815
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

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plastic properties
breast
chromatin
Plasticity
drugs
cancer
inhibitors
Breast Neoplasms
Chromatin
Phosphatidylinositol 3-Kinases
Pharmaceutical Preparations
markers
cells
Chromatin Assembly and Disassembly
Genomic Instability
Differentiation Antigens
Mitogen-Activated Protein Kinase Kinases
Cell death
Heterografts
Epigenomics

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Differentiation-state plasticity is a targetable resistance mechanism in basal-like breast cancer. / Risom, Tyler; Langer, Ellen M.; Chapman, Margaret P.; Rantala, Juha; Fields, Andrew J.; Boniface, Christopher; Alvarez, Mariano J.; Kendsersky, Nicholas D.; Pelz, Carl R.; Johnson-Camacho, Katherine; Dobrolecki, Lacey E.; Chin, Kwang-Yung; Aswani, Anil J.; Wang, Nicholas J.; Califano, Andrea; Lewis, Michael T.; Tomlin, Claire J.; Spellman, Paul; Adey, Andrew; Gray, Joe; Sears, Rosalie.

In: Nature Communications, Vol. 9, No. 1, 3815, 01.12.2018.

Research output: Contribution to journalArticle

Risom, T, Langer, EM, Chapman, MP, Rantala, J, Fields, AJ, Boniface, C, Alvarez, MJ, Kendsersky, ND, Pelz, CR, Johnson-Camacho, K, Dobrolecki, LE, Chin, K-Y, Aswani, AJ, Wang, NJ, Califano, A, Lewis, MT, Tomlin, CJ, Spellman, P, Adey, A, Gray, J & Sears, R 2018, 'Differentiation-state plasticity is a targetable resistance mechanism in basal-like breast cancer', Nature Communications, vol. 9, no. 1, 3815. https://doi.org/10.1038/s41467-018-05729-w
Risom, Tyler ; Langer, Ellen M. ; Chapman, Margaret P. ; Rantala, Juha ; Fields, Andrew J. ; Boniface, Christopher ; Alvarez, Mariano J. ; Kendsersky, Nicholas D. ; Pelz, Carl R. ; Johnson-Camacho, Katherine ; Dobrolecki, Lacey E. ; Chin, Kwang-Yung ; Aswani, Anil J. ; Wang, Nicholas J. ; Califano, Andrea ; Lewis, Michael T. ; Tomlin, Claire J. ; Spellman, Paul ; Adey, Andrew ; Gray, Joe ; Sears, Rosalie. / Differentiation-state plasticity is a targetable resistance mechanism in basal-like breast cancer. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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