Abstract B023: Identifying therapeutic vulnerabilities in metastatic prostate cancer transcriptional phenotypes

Abstract Background: Androgen-targeted therapy, chemotherapy and 177Lu-PSMA radioligand therapy have improved metastatic prostate cancer (mPC) patient survival. However, most patients develop resistance to these therapies. Studying genomic and transcriptomic changes that cause resistance requires repeated sample collection and is not suited to traditional invasive tissue biopsy techniques. We have developed a liquid-biopsy based technique to isolate cell-free DNA (cfDNA) and circulating tumor cell (CTC) RNA from mPC patients enabling genomic and transcriptomic profiling. Transcriptomic profiling of 146 high tumor purity mPC CTC samples from 70 patients identified 4 transcriptional phenotypes driven by changes in luminal, AR and proliferative signaling pathways: Low Proliferation (LP, n= 12, low luminal/AR/proliferation) Luminal A (LumA, n=24, high luminal/AR, low proliferation). Luminal B (LumB, n=31, high luminal/AR/proliferation) and Neuroendocrine Prostate Cancer (NEPC, n=3, low luminal/AR, high proliferation). Compared to LP and LumA, the LumB phenotype is associated with shorter overall survival and early progression on 177Lu-PSMA highlighting an unmet need for treatment options in patients with LumB CTCs. Here, we use mPC CTC transcriptional profiling to identify drivers of proliferation and treatment resistance in the LumB phenotype. Methods: Blood was collected from patients with mPC receiving standard of care treatment. CTCs were purified using immunomagnetic capture on a microfluidic platform, subjected to RNA-seq analysis and assessed for transcriptional phenotypes and gene expression signatures. Results: We compared expression of gene sets related to established tumor suppressors or oncogenic drivers, DNA damage repair by homologous recombination repair (HRR), and cell cycle drivers in LP, LumA and LumB CTC phenotypes. LumB CTC samples display elevated expression of cell cycle genes related to S/G2/M phase progression (CCNE1, CCNA2 and CCNB1), but not G1 phase progression (CCND1 or CCND3), suggesting that increased S/G2/M progression is contributing to increased proliferation. In preclinical models, CCNE1 overexpression causes genomic instability and activation of DNA damage repair, cell cycle checkpoints and a S/G2/M phase transcriptional program mediated by the MYBL2-FOXM1 transcription factor complex. Indeed, we also observe increased expression of HRR, cell cycle checkpoint and MYBL2-FOXM1 transcriptional signatures in LumB subtypes. Conclusions: CTC transcriptional profiling has identified an aggressive and treatment resistant LumB phenotype characterized by high expression of genes involved in S/G2/M cell-cycle progression, HRR and cell cycle checkpoints. These findings suggest that elevated cell cycle progression and upregulated DNA repair capability may underlie the aggressive behavior and therapeutic resistance observed in patients with LumB CTCs. Ongoing efforts are focused on developing preclinical models of the mPC CTC transcriptional phenotypes to identify therapeutic vulnerabilities specific to the LumB subtype. Citation Format: David Gallo, Jamie M. Sperger, Amy K. Taylor, Kristen Rosche, Viridiana Carreno, Alex H. Chang, Emily Abella, Kaitlin Durnen, Muhammad Dar, Charlotte Linebarger, William M. Stump, Kendra Marr, Kyle T. Helzer, Matthew L. Bootsma, Grace C. Blitzer, John M. Floberg, David Kosoff, Rana R. McKay, Wei X. Xiao, Shuang G. Zhao, Joshua M. Lang, Marina N. Sharifi. Identifying therapeutic vulnerabilities in metastatic prostate cancer transcriptional phenotypes [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 B023.