Pre-clinical studies of epigenetic therapies targeting histone modifiers in lung cancer

Abstract

Treatment options for lung cancer patients have been generally limited to standard therapies or targeted interventions which involve a small number of known mutations. Although the targeted therapies are initially successful, they most often result in drug resistance, relapse, and mortality. We now know that the complexity of lung cancer comes not only from genomic changes, but also from aberrant epigenetic regulatory events. Epigenetic therapies have shown promise as single agents in the treatment of hematological malignancies but have yet to meet this expectation in solid tumors thus fostering researchers to pursue new approaches in the development and use of epigenetic interventions. Here, we review some recent pre-clinical findings involving the use of drugs targeting histone modifying enzymes both as single agents and as co-therapies against lung cancer. A greater understanding of the impact of these epigenetic compounds in lung cancer signaling is needed and further evaluation in vivo is warranted in several cases based on the pre-clinical activity of a subset of compounds discussed in this review, including drugs co-targeting HDACs and EGF receptor, targeting Brd4 and targeting Jumonji histone demethylases.

Keywords: BRD4; EZH2 inhibitors; HDAC inhibitors; Jumonji demethylases; Jumonji inhibitors; epigenetic therapeutics; lung cancer; pre-clinical studies.

Figure 1

Schematic representation of the mechanism of action of select histone modifying compounds tested on the lung cancer epigenome. DZNep lowers EZH2 protein levels, decreasing polycomb complex activity and H3K27 methylation. JIB-04 inhibits the enzymatic activity of Jumonji histone demethylases, blocking the demethylation of tri and dimethylated histone lysines and decreasing tumor growth in vivo, while LSD1 inhibitors block the demethylation of monomethylated lysines. JQ1 prevents BRD4 binding to histones at acetylated lysines. HDAC inhibitors prevent the deacetylation of lysines, increasing acetylation and keeping chromatin in a more open, transcriptionally competent conformation.