Abstract

Acquired somatic copy number alterations are frequently associated with the selection of drug resistant oncogenes. However, precise mechanisms driving selection of distinct regions within the genome remains unclear. In recent years, we have established that chromatin states and lysine demthylases play critical roles in modulating copy gains of drug resistant regions of the genome. Specifically, we have identified the histone tri-demethylase KDM4A as the first enzyme capable of promoting site-specific copy number changes. KDM4A overexpression promotes localised copy gain without global chromosome instability. Tumours 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. KDM4A alters heterochromatin and increases the amount of replication machinery at target loci. These copy gains occur during S phase and are removed as cells are exiting S phase. The cytoband gains are affiliated with drug resistant tumours; 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 tumours and established that these events are targetable through inhibition of chromatin regulators.

- Copy gains are a regulated process

- Copy gains are regulated by KDM4A and histone methylation

- Copy gains are druggable

- Identify input pathways modulating copy gain