TP53 and adenocarcinoma: 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).