Abstract 452: ORIC-944, a PRC2 inhibitor with best-in-class properties, restores luminal features and restricts adaptation in prostate cancer models, conferring synergy with AR pathway inhibitors
Abstract
Polycomb repressive complex 2 (PRC2) silences transcription by tri-methylating histone H3 at lysine 27 (H3K27me3), regulating cell growth and differentiation. The EED subunit is required for chromatin recruitment and histone methyltransferase activity. PRC2 dysregulation is linked to poor prostate cancer prognosis, promotes lineage plasticity and therapeutic resistance. Combining androgen receptor pathway inhibitors (ARPI) with PRC2 inhibitors may overcome or prevent resistance, with clinical trials showing promise in metastatic castration-resistant prostate cancer. First-generation PRC2 inhibitors exhibit poor drug properties and short half-lives, requiring at least twice daily dosing at high doses. ORIC-944 is a second-generation allosteric inhibitor of PRC2 that binds EED and exemplifies best-in-class drug properties including potency, solubility, and ADME/PK, with half-life supporting once daily dosing. The mechanism of PRC2 in prostate cancer lineage plasticity was explored with RNA-seq, H3K27me3 ChIP-seq, and ATAC-seq data from in vitro and in vivo studies of ORIC-944 as a single agent and combined with ARPI. No evidence for a non-canonical EZH2 role was found comparing EZH2 and EED inhibitors by RNAseq. ORIC-944 or EZH2 inhibition led to robust PRC2 inhibition, luminal state transition, and increased AR signaling in a spectrum of AR-positive in vivo prostate cancer models. In vivo kinetic studies revealed that luminal cell state transition and increased AR signaling…
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