Abstract
Members of the KDM5 histone H3 lysine 4 demethylase family are associated with therapeutic resistance, including endocrine resistance in breast cancer, but the underlying mechanism is poorly defined. Here we show that genetic deletion of KDM5A/B or inhibition of KDM5 activity increases sensitivity to anti-estrogens by modulating estrogen receptor (ER) signaling and by decreasing cellular transcriptomic heterogeneity. Higher KDM5B expression levels are associated with higher transcriptomic heterogeneity and poor prognosis in ER+ breast tumors. Single-cell RNA sequencing, cellular barcoding, and mathematical modeling demonstrate that endocrine resistance is due to selection for pre-existing genetically distinct cells, while KDM5 inhibitor resistance is acquired. Our findings highlight the importance of cellular phenotypic heterogeneity in therapeutic resistance and identify KDM5A/B as key regulators of this process.
Original language | English |
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Pages (from-to) | 939-953.e9 |
Journal | Cancer Cell |
Volume | 34 |
Issue number | 6 |
DOIs | |
State | Published - 10 Dec 2018 |
Externally published | Yes |
Keywords
- acquired resistance
- barcoding
- cellular heterogeneity
- endocrine resistance
- epigenetic
- KDM5B
- pre-existing resistance
- single-cell RNA-seq
- subclonal fraction
- transcriptomic heterogeneity
ASJC Scopus subject areas
- Oncology
- Cancer Research