# Defining the heterogeneous molecular landscape of lung cancer cell responses to epigenetic inhibition

## TL;DR

This study explores how different lung cancer cells respond to epigenetic drugs, revealing both shared and unique molecular changes.

## Contribution

The paper provides a comprehensive multi-omics dataset profiling HDAC inhibitor responses in non-isogenic cancer cell lines.

## Key findings

- HDACi-regulated proteins show consistent and divergent effectors across cell lines.
- Quantitative profiling reveals coordinated molecular remodeling in treated cancer cells.
- A web interface is provided to explore the extensive dataset for drug perturbation analysis.

## Abstract

Epigenetic inhibitors exhibit powerful antiproliferative and anticancer activities. However, cellular responses to small-molecule epigenetic inhibition are heterogeneous and dependent on factors such as the genetic background and metabolic state of cells, as well as on-/off-target engagement of individual small-molecule compounds. The molecular study of the extent of this heterogeneity often measures changes in a single cell line. To more comprehensively profile the effects of small-molecule perturbations and their influence on heterogeneous cellular responses, we present a molecular resource based on the quantification of chromatin, proteome, and transcriptome remodeling due to histone deacetylase inhibitors (HDACi) in non-isogenic cell lines. Through quantitative molecular profiling of 10,621 proteins, these data reveal coordinated molecular remodeling of HDACi treated cancer cells. HDACi-regulated proteins differ greatly across cell lines with consistent (JUN, MAP2K3, CDKN1A) and divergent (CCND3, ASF1B, BRD7) cell-state effectors. Together these data provide valuable insight into cell-type driven and heterogeneous responses that must be taken into consideration when monitoring molecular perturbations in culture models. We have also built a web interface for the extensive amount of data to allow users to explore the data as a resource for understanding chemical perturbation of diverse cell types.

Quantitative multi-omics profiling of HDAC inhibitor responses in non-isogenic cancer cell lines reveals shared and divergent molecular remodeling. Responses highlight cell-type-dependent and -independent epigenetic drug mechanisms of action.