To evaluate this hypothesis, we leveraged previously described prostate models of targeted therapy-induced adenocarcinoma-to-NE transformation.3,18 Double knock out (DKO) of TP53 and RB1 in the PRAD cell lines LnCap/AR and 22PC facilitates acquired resistance to AR-targeted therapy such as enzalutamide in vivo, together with a loss of epithelial features and increased NE marker expression.3,18 We treated xenografts of these models in immunocompromised mice with enzalutamide, simurosertib or both agents (Fig. 3a and Supplementary Fig. 4a). Here, TP53 is linked to prostate adenocarcinoma.