Epigenetics Impacts Copy Number Heterogeneity and Drug Resistant Gene Selection

Copy number heterogeneity is a feature of tumors and associates with acquired drug resistance. The mechanistic bases for copy number heterogeneity, especially selection of specific regions within the genome, are unknown. We have recently identified the histone tri‐demethylase KDM4A as the first enzyme capable of promoting site‐specific copy number changes. KDM4A overexpression as well as stabilization promotes localized copy gain without global chromosome instability. Tumors with increased KDM4A levels are enriched in copy gains for cytobands observed in cell culture models. We further demonstrate that these events are the result of rereplication. These copy gains occur during S phase and are removed as cells are exiting S phase. The cytoband gains are affiliated with drug resistant tumors; therefore, we asked whether targeting the copy gains through chemical inhibition of KDM4A was possible and whether a chemical screen could demonstrate that an active process is associated with elimination of copy gained regions. Our most recent data demonstrates the druggability of these processes. In fact, we have now identified small molecules that impact KDM4A and copy gain as well as the ability to remove gains during cell cycle progression. Lastly, a screen for environmental and chemical agents has uncovered input signals that are responsible for generating site‐specific gains through altering the chromatin environment. Taken together, we have identified genetic, epigenetic and environmental factors promoting copy number heterogeneity in tumors and established that these events are targetable through inhibition of chromatin regulators. Support or Funding Information NIH/NIGMS Leukemia and Lymphoma Society American Cancer Society American Lung Association Alex Lemonade Stand Foundation