# Epigenetic mechanisms of therapeutic resistance

> **NIH NIH P01** · DANA-FARBER CANCER INST · 2020 · $366,097

## Abstract

Project Summary/Abstract
Cellular phenotypic heterogeneity is a key mechanism underlying neoplastic disease progression and
therapeutic resistance, yet its regulation is poorly understood at the molecular level. We have found that elevated
therapeutic resistance is associated with higher levels of cell-to-cell transcriptomic heterogeneity and that
decreasing such heterogeneity by modulating the activity of epigenetic histone-modifying enzymes such as
KDM5B improves responses to treatment. We also determined that acquired resistance to epigenetic drug
agents, including KDM5 and BET bromodomain inhibitors, is due to epigenetic mechanisms, whereas acquired
endocrine resistance reflects a selection for a pre-existing, genetically distinct sub-populations of cells. The goal
of this Project is to investigate the population dynamics of cellular phenotypic heterogeneity in response to and
resistance to cancer therapies in luminal estrogen receptor positive (ER+) and triple-negative breast cancer
(TNBC). Our hypothesis is that cellular states governed by epigenetic regulators are highly variable and dynamic
and that this underlies acquired therapeutic resistance. We also hypothesize that by modulating the activity of
epigenetic regulators and by identifying mechanisms of synthetic lethality and the acquired resistance to
epigenetic agents, we can decrease transcriptomic heterogeneity and improve therapeutic response. To test our
hypotheses, we will characterize the impact of genetic and epigenetic heterogeneity on acquired resistance to
endocrine, chemo-, and epigenetic therapies (Aim 1). We will use barcoded cells to follow population dynamics
during the development of acquired resistance, characterize the epigenetic landscape and transcriptomic
heterogeneity of drug-tolerant and -resistant populations, and build mathematical models based on experimental
data to predict the evolution of therapeutic resistance to different agents. Additionally, to define synthetic-lethal
interactions and mechanism of acquired resistance to epigenetic therapies we will perform CRISPR/Cas9
screens (Aim 2) in ER+ and TNBC cell lines that are sensitive versus resistant to epigenetic agents. Overall, the
project will significantly advance our knowledge of the regulation of phenotypic heterogeneity and the role this
plays in therapeutic responses and resistance.

## Key facts

- **NIH application ID:** 10023397
- **Project number:** 1P01CA250959-01
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** KORNELIA POLYAK
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $366,097
- **Award type:** 1
- **Project period:** 2020-09-11 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10023397

## Citation

> US National Institutes of Health, RePORTER application 10023397, Epigenetic mechanisms of therapeutic resistance (1P01CA250959-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10023397. Licensed CC0.

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