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

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.

A Mechanism for Epithelial-Mesenchymal Heterogeneity in a Population of Cancer Cells

“…While the model does not capture the rich behavior that may arise from the variable strengths of regulatory interactions in cells in a population or from cell-cell communication, it is a useful first step in understanding the generation and maintenance of phenotypic heterogeneity in cancer cells. Targeting the ability of cancer cells to change phenotypes and generate heterogeneous populations has recently been proposed as a therapeutic strategy for combating drug resistance (Risom et al, 2018). Our model can be a platform to identify putative therapeutic targets for inhibiting the generation, maintenance, and propagation of phenotypic heterogeneity in cancer cells that exhibit EMP.…”

“…Spontaneous switching between luminal, basal, and stem-like states has been reported in breast cancer cell lines (Gupta et al, 2011) while androgen-deprivation therapy has been shown to promote transition to a neuroendocrine phenotype in prostate cancer (Hirano et al, 2004;Wright et al, 2003). Cancer cells with different phenotypes can exhibit different sensitivities to various drugs and therapeutic regimens (Risom et al, 2018;Wooten et al, 2018). Therefore, non-genetic mechanisms of phenotypic heterogeneity and plasticity in cancer cells are a fundamental challenge to anti-cancer therapies and an understanding of such mechanisms is essential to the development of effective anti-cancer treatments.…”

“…Celià -Terrassa et al observed hysteresis in the dynamics of EMP in multiple normal and cancerous mammary epithelial cell lines and reported a role for hysteretic dynamics in the metastatic ability of cancer cells (Celià-Terrassa et al, 2018). Risom et al showed that drugs targeting specific cellular pathways alter the transitions between epithelial-like and mesenchymal-like states in breast cancer cell lines, thereby establishing phenotypic plasticity as a therapeutically targetable property (Risom et al, 2018). The mechanism responsible for the phenotypic heterogeneity and plasticity in cancer cells, however, remains uncharacterized.…”

“…The mechanism responsible for the phenotypic heterogeneity and plasticity in cancer cells, however, remains uncharacterized. Some studies have described phenomenological models of phenotypic plasticity in cancer cells (Chapman et al, 2019;Gupta et al, 2011;Risom et al, 2018). While predictions from these models fit the experimental data reported in the respective studies, such models lack detailed biomolecular mechanistic bases.…”

Adaptive response to BET inhibition induces therapeutic vulnerability to MCL1 inhibitors in breast cancer

“…Reduction in cellular robustness, cell cycle progression, DNA damage response and induction of replication stress have been proposed as underlying mechanisms of response to BET inhibition (15,(17)(18). BET molecules also regulate cellular plasticity as exemplified by the emergence of drug-tolerant persistent cells with BRD4 dependence and altered differentiation states after MEK and PI3K/mTOR inhibition in TNBC (19). The adaptive responses and therapeutic stress such as DNA-damage associated with inhibition of BET activity provide an unexplored opportunity to discover drug-induced vulnerabilities, which might be exploited with effective combination therapies (20).…”