Metastatic prostate cancer develops resistance to antiandrogen therapy through mechanisms, including lineage plasticity. Leveraging published genomic datasets, Mu and colleagues functionally validated roles for concomitant TP53 and RB1 loss in promoting phenotypic flexibility. Combined loss of TP53 and RB1 enabled prostate cancer cells to switch from an androgen receptor (AR)dependent luminal identity to a more basal state no longer requiring AR activity. SOX2, through its reprogramming

more »

... ty, was identified as the primary driver of this adaptive transition, with silencing restoring antiandrogen sensitivity. Thus, SOX2-driven lineage plasticity caused by mutations in TP53 and RB1 represents a novel resistance mechanism to antiandrogen therapy in prostate cancer and might enable the design of more effective therapeutic strategies. (Image courtesy of Wikimedia Commons.