Abstract PR008: Molecular determinants of prostate cancer lineage plasticity

Abstract

Abstract Androgen deprivation therapy (ADT) has been an effective treatment for advanced prostate cancer (PCa) for decades because PCa retains the lineage specific dependence of normal prostate tissue on androgen receptor (AR) signaling. Unfortunately, nearly all patients will progress through ADT with castrate resistant prostate cancer (CRPC). CRPC is typically associated with reactivation of AR signaling despite ADT. However with widespread clinical deployment of potent AR signaling inhibitors, an increasing fraction of CRPCs (~20) are now observed to lose AR signaling activity and show gene expression patterns consistent with alternative lineage states. These lineage variants share clonal origin with the pre-existing adenocarcinoma, so some PCa cells have sufficient plasticity to reprogram to an AR independent lineage state like neuroendocrine prostate cancer (NEPC) that is recalcitrant to available therapies. The molecular determinants of prostate cancer lineage plasticity are incompletely defined, and this knowledge gap has hindered development of diagnostic and therapeutic approaches necessary to identify and treat prostate cancer lineage plasticity. We present results from experiments testing the contribution of EZH2 and NOTCH signaling to prostate cancer lineage plasticity and NEPC reprogramming. EZH2 expression is elevated in advanced PCa, particularly NEPC, suggesting it drives lineage reprogramming. However, using genetically engineered mice and organoids we find that EZH2 is not required for NEPC reprogramming that occurs in some PCa cells in the absence of the RB1 and TP53 tumor suppressor genes. EZH2 deficiency does alter multi-lineage prostate cancer plasticity, biasing development towards lineage variants observed clinically including amphicrine and double negative prostate cancer. In contrast, data from clinical specimens indicates NOTCH signaling activity declines in NEPC compared to AR+ CRPC. NOTCH signaling suppresses NEPC development in both organoids and genetically engineered mice, and loss of NOTCH signaling is required to maintain the NEPC lineage state. Constitutive NOTCH signaling biases PCa development towards unique lineage variants including AR positive metastatic PCa with luminal differentiation. These results identify EZH2 and NOTCH signaling as molecular determinants of PCa lineage plasticity and NEPC reprogramming with implications for ongoing efforts to target these molecules for PCa therapy. Citation Format: Kristine Wadosky, Sheng-Yu Ku, Yanqing Wang, Xiaojing Zhang, Jie Wang, Jianmin Wang, Himisha Beltran, David W. Goodrich. Molecular determinants of prostate cancer lineage plasticity [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr PR008.