MP51-14 ORIGIN OF A MESENCHYMAL AND STEM-LIKE SUBTYPE OF METASTATIC CASTRATION-RESISTANT PROSTATE CANCER

Abstract

INTRODUCTION AND OBJECTIVE: Potent androgen receptor (AR) signaling inhibitors, such as enzalutamide and abiraterone, have transformed the management of metastatic castration-resistant prostate cancer (M-CRPC) and can induce durable responses in a fraction of patients. However, the remainder exhibit a transient and often partial response or are completely insensitive to therapy. Molecular subtyping based on transcriptional profiling can provide important biological and clinical insights. Yet, there is no widely accepted molecular subtyping of M-CRPC. METHODS: To generate a more powerful and biologically relevant subtyping of M-CRPC, we have built a new molecular classification by transcriptomic clustering. We used a compiled dataset (total n=94) of patient-derived xenografts (PDXs), cell lines, organoids, and organoid-derived xenografts as a training set for generating clusters, which we then validated in independent M-CRPC datasets. RESULTS: We found three clusters, which we named after their top-enriched gene sets: AR-active tumors (ARPC), neuronal progenitor tumors (NEPC), and mesenchymal/stem-like tumors (MSPC). Genetically, ARPC was enriched of AR mutations and chromosome 8p23 deletion. MSPC was enriched of chromosome 3q26 amplifcation, and NEPC was enriched of Rb deep deletion. Interestingly, paradoxcially, the potent AR blockers could induce reprogramming of ARPC to MSPC, suggesting that epithelial plasticity contributes to the emergence of MSPC. Mechanistically, treatment of PTEN-null TP53 wild-type prostate cancer cells with enzalutamide induced rapid acquisition of mesenchymal and stem cell traits via rapid transcriptional repression of TP53. We found that activation of HER2 signaling by exogenous neuregulin-1 can reactivate the transformed cells from growth arrest or dormancy, and the cancer cells generated liver metastasis. HER2 inhibition by neratinib were able to block tumor growth particularly in combination with enzalutamide. CONCLUSIONS: Metastatic CRPCs can be subdivided into three subtypes, ARPC, MSPC and NEPC. AR inhibitor induced subtype conversion from ARPC to MSPC via inactivation of TP53. Cells in the MSPC state were particularly vulnerable to HER2 inhibitor neratinib when combined with enzalutamide.