Abstract LB291: Monitoring and targeting therapy resistance mediating neuroendocrine trans-differentiation in breast cancer via the neurod1/ncam axis

Abstract Neuroendocrine breast carcinoma (NEBC) is a rare, aggressive subtype of breast cancer known for its high resistance to therapies. Unlike prostate, pulmonary, or gastroenteropancreatic tumors where neuroendocrine trans-differentiation (NED) is recognized as a key driver of intra-tumoral heterogeneity and treatment resistance, NEBC remain poorly characterized. Its rarity, combined with its emergence predominantly as a relapse-associated therapy escape mechanism, presents significant challenges for research and clinical management. Neuroendocrine transdifferentiation underscores the remarkable plasticity of cancer cells under therapeutic pressure. The absence of robust patient-derived NEBC models further hampers progress in understanding this resistant state and developing effective interventions. In addition, beyond synaptophysin detection through histopathological analysis, there are limited actionable biomarkers to clinically detect or monitor NEBC appearance post-treatment.To investigate neuroendocrine-mediated resistance, we leveraged our recently developed Circulating Tumor Cell (CTC)-organoid platform and established unique patient-derived organoid (PDO) models that faithfully mirror the key features of NEBC, including its intra-tumoral heterogeneity and multidrug resistance. Through comparative analysis of matched epithelial and neuroendocrine PDOs derived from distinct sites of the same patient tumor, we uncovered distinct molecular and genetic profiles that offer valuable insights into NEBC biology and resistance mechanisms. While both cell types shared some genetic alterations (e.g., ERBB2 and MYCN amplification, TP53 loss), NEBC cells exhibited unique additional genomic rearrangements and downregulated ERBB2 expression. Multi-omics data integration allowed us to identify the transcription factor NEUROD1 as a key driver of neuroendocrine reprogramming. Moreover, our findings indicate that the NEUROD1 downstream target neural cell adhesion molecule (NCAM) serves as a potential biomarker for stratifying NEBC patients, detectable through NCAM-expressing CTCs in liquid biopsies. Additionally, a comprehensive drug screen revealed that NEBC cells are particularly sensitive to CDK4/6 and FGFR inhibitors. Collectively, by integrating NCAM expression on circulating CTCs analysis, we introduce a novel diagnostic tool possibly enabling early and longitudinal detection of treatment resistant NED cells. Our preclinical data also identified promising novel therapeutic avenues, such as CDK4/6 inhibition, which should be further explored for the management of the complex disease state of neuroendocrine breast cancer.1 Würth, R., et al. Circulating tumor cell plasticity determines breast cancer therapy resistance via neuregulin 1-HER3 signaling (2025). Nature Cancer, Jan 3. doi: 10.1038/s43018-024-00882-2 Citation Format: Roberto Würth, Tasneem Cheytan, Paul Schwerd-Kleine, Ewgenija Gutjahr, Martin Sprick, Andreas Trumpp. Monitoring and targeting therapy resistance mediating neuroendocrine trans-differentiation in breast cancer via the neurod1/ncam axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB291.