Co‐targeting driver pathways in prostate cancer: two birds with one stone

Co‐targeting strategies strive to improve cancer outcomes by combining therapies under contextualized genetic and environmental conditions that selectively target exploitable alterations in tumor cells. Adaptive survival pathways triggered by inhibition of driver genes in the androgen receptor (AR) or PI3K/AKT pathways are of great interest, since they are among the most frequently altered in castrate‐resistant prostate cancer (CRPC). Unfortunately, negative feedback loops exist between the AR and PI3K/AKT pathways such that targeting AR leads to activation of PI3K/AKT signaling, while PI3K/AKT pathway inhibition leads to increased AR transcriptional activity. Hence, targeting both pathways provides an opportunity for conditional lethality and a high therapeutic index. In this issue of EMBO Molecular Medicine, Yan et al (2018) present an elegant study showing that histone deacetylase 3 (HDAC3) acts as a common upstream activator of both AR and AKT signaling pathways, and use HDAC3 inhibitors as a monotherapy to co‐target two major pathways driving CRPC growth.