Abstract A036: Multi-Omic Profiling Clarifies Mechanisms of Therapy-Induced Prostate Cancer Lineage Plasticity

Abstract Background: Prostate adenocarcinomas are the most common form of the disease. Targeting the androgen receptor (AR) is the principal treatment strategy. However, resistance is common. Lineage plasticity (LP)—change in differentiation state—is increasingly recognized as a mechanism of resistance to AR-targeting therapies. LP is a continuum ranging from amphicrine to neuroendocrine prostate cancer (NEPC). Despite the increasing incidence of LP due to more widespread use of new and potent AR inhibitors, mechanisms by which LP emerges after therapy have been understudied due to paucity of matched patient tumors. To address this deficit, we performed multi-omic profiling on matched biopsies from 16 patients, including seven patients that underwent LP after treatment. Methods: We used DNA sequencing to identify mutations and copy number alterations present in tumors at baseline and at progression. We also performed RNA sequencing and transcriptional subtyping of all tumors. Results: Analysis of RNA sequencing revealed two distinct subtypes of LP in our cohort—most consistent with amphicrine or NEPC. DNA sequencing identified TP53 and RB1 alteration patterns in baseline tumors that eventually underwent specific LP trajectories. Pathways linked to proliferation and inflammatory signaling were highly activated in baseline tumors that eventually underwent LP. Conclusions: Our analysis identified distinct LP trajectories linked with specific genomic and transcriptomic features at baseline. Profiling tumors with this approach may provide clues about which patients may be at greatest risk for undergoing specific LP trajectories after therapy. Citation Format: Anbarasu Kumaraswamy, Visweswaran Ravikumar, Ryan J. Rebernick, Eva Rodansky, Amina Tanweer, Joel A. Yates, Aaron M. Udager, Marcin P. Ceislik, Arvind Rao, Zachery R. Reichert, Arul M. Chinnaiyan, Joshi J. Alumkal. Multi-Omic Profiling Clarifies Mechanisms of Therapy-Induced Prostate Cancer Lineage Plasticity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr A036.