ONECUT2: a validated drug target and lineage plasticity driver in prostate cancer and other malignancies

The CUT/Hox transcription factor ONECUT2 (OC2) promotes lineage plasticity and is a confirmed therapeutic target in prostate cancer and several other malignancies where cell phenotype plays a substantial role in treatment resistance. OC2 governs a broad growth and lineage identity process in prostate cancer that promotes neuroendocrine (NE) differentiation, androgen receptor (AR) suppression, and the emergence of a wide range of treatment-resistant pathways. The mode of action of OC2 includes incorporation of the protein into transcription complexes at gene promoters as an activator and repressor, alteration of chromatin accessibility and epigenetic marks, and extensive alteration of large-scale chromatin modifications, such as super-enhancers and chromatin loops. Notably, OC2 may be unique among NE drivers in that it can promote AR indifference in adenocarcinoma as a direct upstream activator of the glucocorticoid receptor, thus assuming indirect control of a portion of the AR cistrome. OC2 expression and activity increase substantially following hormone therapy in association with aggressive disease in prostate and breast cancer. Experiments in model systems have shown that OC2 has a survival function in both human castration-sensitive and castration-resistant prostate cancer cells. OC2 can be targeted directly with a family of novel small-molecule inhibitors that show therapeutic efficacy in vivo in prostate, breast, and gastric cancer models, including regression of established distant metastases in mice. These findings suggest that inhibition of OC2 clinically may confer substantial therapeutic benefit in some aggressive malignancies, including in localized hormone-sensitive disease.