EZH2 as a therapeutic target in solid tumors

Abstract

Epigenetic alterations are an important hallmark of cancer, and the enzymes that modify histone tails have emerged as attractive drug targets. The histone methyltransferase EZH2 is the catalytic subunit of PRC2, a highly conserved protein complex that regulates gene expression by methylating lysine 27 on histone H3. EZH2 is frequently overexpressed in cancer, and oncogenic gain-of-function mutations have been identified in both hematological malignancies and solid tumors. In cancer cells, the aberrant activity of the enzyme contributes to tumorigenesis by altering cell fate decisions and regulating pathways involved in proliferation, differentiation, and cell migration. Early validation efforts relied on the use of RNAi technology and non-specific small molecule inhibitors to down-regulate EZH2 and destabilize the PRC2 complex. The discovery of catalytic inhibitors of EZH2 has provided an invaluable tool for further elucidating the role of this enzyme in cancer, and preclinical studies in EZH2-mutant non-Hodgkin lymphoma have driven the clinical development of these agents. This review focuses on the use of catalytic small molecule inhibitors to identify solid tumor indications that are dependent on aberrant EZH2 methyltransferase activity. The emerging data suggests that EZH2 inhibitors will have therapeutic potential that extends beyond hematological malignancies to the solid tumor setting.