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.
Highlights
Intratumoral heterogeneity in cancers arises from genomic instability and epigenomic plasticity and is associated with resistance to cytotoxic and targeted therapies
We demonstrate that combination treatment with JQ1, an inhibitor of bromodomain and extraterminal (BET) family proteins including BRD4, can prevent the global change in open chromatin architecture that accompanies drug tolerant persister (DTP) state formation during PI3K/mTOR inhibitor response
We examined the relationship between differentiation-state heterogeneity and breast tumor subtype in primary patient samples, patient-derived xenografts (PDX), and breast cancer cell lines (BCCLs)
Summary
Intratumoral heterogeneity in cancers arises from genomic instability and epigenomic plasticity and is associated with resistance to cytotoxic and targeted therapies. While DNA methylation plays a predominant role in early lineage distinction in the maturing embryo[8], cell differentiation from stem cell states in the adult is primarily carried out through dynamic changes in histone modifications at promoters and distal regulatory elements[2,9,10], altering the open chromatin architecture and providing enhanced expression of new lineage and differentiation genes[11,12]. These chromatin dynamics are critical for the specialized cell state heterogeneity that maintains normal mammary gland function. Our study demonstrates that triple-negative (TN) and basal-like breast cancers show high cell-state heterogeneity and plasticity, and advances our understanding of how drug combinations targeting chromatin dynamics can improve management of these aggressive subtypes of breast cancer
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