Abstract 6545: Reversing lineage plasticity and drug resistance in lethal prostate cancer

Abstract Although major mechanisms of resistance to targeted therapies include mutation of the drug target, recent evidence suggests cell-adaptive mechanisms as alternative avenues for escaping treatment. In several cancers, tumor cells become plastic in response to target inhibition, changing their identity and molecular programs without acquiring further mutations. In the case of castration-resistant prostate cancer (CRPC) treated with standard-of-care, next-generation anti-androgens enzalutamide, tumor cells often switch lineage to survive drug pressure, acquiring neuroendocrine (NE) features and thereby transforming into neuroendocrine prostate cancer (CRPC-NE). Existing targeted therapies for CRPC and CRPC-NE provide limited benefit, representing an unmet clinical need. Hence, the elucidation of tumor plasticity and consequent heterogeneity that contribute to drug resistance is of paramount importance to identify novel therapeutic opportunities. We have recently developed a network-based precision cancer medicine framework to characterize molecular and drug sensitivity profiles of ~100 Genetically-Engineered Mouse Models (GEMM)-derived tumors of prostate cancer (Vasciaveo, et al. 2023). This study revealed that tumors derived from GEMMs with the loss of function of both Pten and Trp53 (NPp53) align with CRPC patients and exhibit high heterogeneity in regulatory programs and histopathologic features, including NE differentiation. We then adopted the NPp53 model to generate several 3D organoid lines in order to study tumor plasticity and heterogeneity. To elucidate their tumors’ regulatory programs, we reverse-engineered genome-wide regulatory networks using multimodal single-cell RNASeq and ATACSeq data to identify Master Regulator (MR) proteins implementing tumor cell identities and characterize their epigenetic landscape. Our network-based regulatory analysis identified several distinct cell populations, including cells activating epithelial-to-mesenchymal (EMT) programs and NE differentiation, all resistant to enzalutamide treatment. Cross-species analysis aligned these cells to human CRPC and CRPC-NE tumors. In particular, our analyses have shed light into the roles of NSD2, a known MR of lethal prostate cancer, whose ablation restored sensitivity to enzalutamide. In summary, we leveraged single-cell, multimodal data from CRPC and CRPC-NE 3D mouse organoids to elucidate regulatory programs of drug resistant, lethal prostate cancer and characterize its heterogeneity. Importantly, we also identified a mechanism that can be exploited for therapeutic intervention to restore tumor cells’ sensitivity Citation Format: Alessandro Vasciaveo, Jia J. Li, Dimitrios Karagiannis, Xiao Chen, Andrea Califano, Chao Lu, Michael M. Shen. Reversing lineage plasticity and drug resistance in lethal prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6545.