Transcriptional Inactivation of TP53 and the BMP Pathway Mediates Therapy-induced Dedifferentiation and Metastasis in Prostate Cancer

Unsupervised clustering and deconvolution analysis identifies three intrinsic subtypes of Metastatic Castration-Resistant Prostate Cancer (M-CRPC): AR pathway-positive Prostate Cancer (ARPC), Neuro Endocrine Prostate Cancer (NEPC), and a novel subtype endowed with hybrid epithelial/mesenchymal (E/M) and luminal progenitor-like traits (Mesenchymal and Stem-like PC, MSPC). Analysis of large patient datasets and in vitro studies support the notion that MSPC originates from ARPC as a consequence of therapy-induced lineage plasticity. Intriguingly, AR blockade instigates two separate and complementary processes: 1) transcriptional silencing of TP53 and hence acquisition of hybrid E/M and stem-like traits; and 2) inhibition of the BMP-SMAD pathway, which promotes resistance to the pro-apoptotic and anti-proliferative effects of AR inhibition. MSPC cell lines and prostate adenocarcinoma cells reprogrammed in vitro to MSPC exhibit a marked dependency on HER2/3 signaling. Moreover, combinations of the panHER inhibitor neratinib with enzalutamide or the mTORC1 inhibitor MLN0128 exhibit efficacy in preclinical models of mixed ARPC/MSPC or MSPC, respectively. Collectively, these results identify a novel subtype of M-CRPC, trace its origin to therapy induced lineage plasticity, and reveal its dependency on HER2/3 signaling.