TY - JOUR
T1 - Differentiation-state plasticity is a targetable resistance mechanism in basal-like breast cancer
AU - Risom, Tyler
AU - Langer, Ellen M.
AU - Chapman, Margaret P.
AU - Rantala, Juha
AU - Fields, Andrew J.
AU - Boniface, Christopher
AU - Alvarez, Mariano J.
AU - Kendsersky, Nicholas D.
AU - Pelz, Carl R.
AU - Johnson-Camacho, Katherine
AU - Dobrolecki, Lacey E.
AU - Chin, Koei
AU - Aswani, Anil J.
AU - Wang, Nicholas J.
AU - Califano, Andrea
AU - Lewis, Michael T.
AU - Tomlin, Claire J.
AU - Spellman, Paul T.
AU - Adey, Andrew
AU - Gray, Joe W.
AU - Sears, Rosalie C.
N1 - Funding Information:
We would like to thank Dr. Megan Troxell of the OHSU Pathology Department for her assistance in obtaining and analyzing primary breast cancer tumor samples from the OHSU Biobank, the Dr. Jay Bradner Lab of the Dana-Farber Cancer Institute for their generous donation of JQ1 for our animal studies, Dr. Dimitri Rozanov for providing cytotoxic therapy screening plates, Dr. Dan Georgess for his assistance with statistics, Elmar Bucher for the generation of data management Python code, and Dr. Jason M. Link for his generation of an image analysis pipeline. We acknowledge Dr. Bob Searles and MPSSR core at OHSU for their sequencing efforts. T.R. was supported by the Ruth L. Kirschtein PMCB T32 Training Grant 5T32GM071338-09, Vertex Pharmaceuticals Scholarship, and Tartar Trust Fellowship. E.M.L. was supported by an ACS postdoctoral fellowship 118795-PF-10-022-01-CSM, M.P.C. was supported by the NSF Graduate Research Fellowship Program and the Berkeley Fellowship for Graduate Study. A.C. was supported by the National Cancer Institute (NCI) Outstanding Investigator Award (R35 CA197745), the NCI Research Centers for Cancer Systems Biology Consortium (U54 CA209997), and two National Institutes of Health (NIH) instrumentation grants (S10 OD012351 and S10 OD021764). C.J.T. is supported by the NIH Center “Systems Biology of Collective Cells Decisions” through Stanford University NIH P50GM107615. R.C.S. is supported by the National Institutes of Health, National Cancer Institute R01 CA129040 and R01 CA100855, the Department of Defense Breast Cancer Research Program BC103625, the Colson Family Foundation, and the Prospect Creek Foundation. R.C.S. and J.W.G. are supported by the NCI U54 grant CA209988. J.W.G. is supported by the National Institutes of Health, National Cancer Institute grant U54 CA112970, by the Susan G. Komen Foundation, and the Prospect Creek Foundation. Sequencing and Flow Cytometry work was performed in OHSU Shared Resources supported by the Knight Cancer Institute Cancer Center Support Grant 5 P30 CA69533.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-05729-w
DO - 10.1038/s41467-018-05729-w
M3 - Article
C2 - 30232459
AN - SCOPUS:85053552123
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3815
ER -