Towards a more precise therapy in cancer: Exploring epigenetic complexity

A plethora of preclinical evidences suggests that pharmacological targeting of epigenetic dysregulation is a potent strategy to combat human diseases. Nevertheless, the implementation of epidrugs in clinical practice is very scarce and mainly limited to haematological malignancies. In this review, we discuss cutting-edge strategies to foster the chemical design, the biological rationale and the clinical trial development of epidrugs. Specifically, we focus on the development of dual hybrids to exploit multitargeting of key epigenetic molecules deregulated in cancer; the study of epigenetic-synthetic lethality interactions as a mechanism to address loss-of-function mutations, and the combination of epidrugs with other therapies such as immunotherapy to avoid acquired chemoresistance and increase therapy sensitivity. By exploring these challenges, among others, the field of epigenetic chemical biology will increase its potential for clinical benefit, and more effective strategies targeting the aberrant epigenome in cancer are likely to be developed both in haematological and solid tumours.The authors thank CERCA Programme/Generalitat de Catalunya for institutional support. Research at M.B. lab is supported by Instituto de Salud Carlos III cofunded by European Regional Development Funds (ERDF/FEDER) a way to build Europe (PI15/00638 and PI18/00910). Research at F.P.C lab is supported by Spanish Ministerio de Ciencia e Innovacion and FEDER (CTQ2016-80375-P and CTQ2014-51912-REDC), by Gobierno Vasco/Eusko Jaurlaritza (IT-324-07) and by 2020 Framework Programme of the European Union (Euro-Cholangio-Net CA18122)