Pharmacological targeting of the cancer epigenome

Abstract

Epigenetic dysregulation is increasingly appreciated as a hallmark of cancer, including disease initiation, maintenance and therapy resistance. As a result, there have been advances in the development and evaluation of epigenetic therapies for cancer, revealing substantial promise but also challenges. Three epigenetic inhibitor classes are approved in the USA, and many more are currently undergoing clinical investigation. In this Review, we discuss recent developments for each epigenetic drug class and their implications for therapy, as well as highlight new insights into the role of epigenetics in cancer.

Figure 1:. Epigenetic Targets in Cancer

Major pharmacologic drug classes that target epigenetic processes and are currently in clinical testing or approved by government regulatory agencies. * indicates FDA approval.

Figure 2:. Therapeutic Targeting of the Epigenome.

A) Wild-type (WT) BAF complex evicts PRC1/PRC2 from chromatin to establish open chromatin regions, while loss of BAF activity (e.g., through loss-of-function (LOF) mutations) results in unopposed PRC2 signaling. B) Epigenetic proteins participate in oncogenic signaling by associating with oncogenic transcription factors.

Figure 3:. New Epigenetic Targets in Cancer

Schematic showing select complexes (PRC1, ENL within the super elongation complex, and ASH1L) that are of interest for the development of new therapeutics.

Figure 4:. Epigenetic/Lineage Plasticity as a mechanism of therapeutic resistance

A) Drug-tolerant tumor cells harbor the intrinsic ability to reversibly alter their gene expression programs to overcome drug treatments. B) Cancer cells can co-opt lineage-associated differentiation states to overcome therapeutic or environmental stressors. C) Inhibition of an epigenetic protein can select for the upregulated activity of an alternative epigenetic pathway.