Neuroendocrine Differentiation Mediates Escape from HER2-Targeted Therapy in Breast Cancer
Neuroendocrine differentiation (NED) promotes lineage plasticity and therapy resistance in prostate and lung cancers. Here we identify NED as a route of treatment escape in breast cancer: neuroendocrine features emerged or increased in 22% of progressive cases, predominantly, but not exclusively, in HER2-positive subtype. Using patient-derived, epithelial/neuroendocrine organoid and xenograft models, we map the epigenetic and transcriptional divergence between epithelial and neuroendocrine states arising from a shared mutational background and define a breast cancer neuroendocrine signature. NED involves epigenetic silencing of EpCAM and amplified HER2, while NEUROD1 functions as a master transcriptional regulator of the neuroendocrine fate. NCAM-positive putative circulating tumor cells were detected in patients in whom EpCAM-based detection had failed. Neuroendocrine tumor cells exhibit an FGFR1 dependency associated with NCAM-FGFR1 interaction and mesenchymal FGFR1 splicing. Together, these findings establish NED as a mechanism of escape from HER2-targeted therapy in breast cancer, with implications for disease monitoring and intervention.
Authors
- Martin Ronald Sprick (ORCID: https://orcid.org/0000-0001-9691-7574)
- Celina V. Wagner (ORCID: https://orcid.org/0000-0002-8312-3617)
- Elisa Donato (ORCID: https://orcid.org/0000-0003-3541-9170)
- Julia Bulkescher (ORCID: https://orcid.org/0009-0000-8507-6511)
- Laura L. Michel (ORCID: https://orcid.org/0000-0002-7784-2826)
- Daria Doncevic (ORCID: https://orcid.org/0000-0001-8089-4187)
- Sarah‐Jane Neuberth (ORCID: https://orcid.org/0009-0008-5853-9910)
- Johannes Betge (ORCID: https://orcid.org/0000-0001-9549-1866)
- Mario Hlevnjak (ORCID: https://orcid.org/0000-0002-7766-0352)
- Theresa Mulholland (ORCID: https://orcid.org/0000-0002-2837-0519)
- Vera Thiel (ORCID: https://orcid.org/0000-0003-1245-0175)
- Carl Herrmann (ORCID: https://orcid.org/0000-0003-4989-4722)
- Polina Y. Kozyulina (ORCID: https://orcid.org/0000-0001-8520-3445)
- Marc Zapatka (ORCID: https://orcid.org/0000-0001-8287-5967)
- Verena Thewes (ORCID: https://orcid.org/0009-0004-6006-4636)
- Michael Scherer (ORCID: https://orcid.org/0000-0001-7990-6179)
- Andreas Trumpp (ORCID: https://orcid.org/0000-0002-6212-3466)
- Ewgenija Gutjahr (ORCID: https://orcid.org/0000-0003-2099-7306)
- Tasneem Cheytan (ORCID: https://orcid.org/0000-0001-8193-4427)
- Jeroen Krijgsveld (ORCID: https://orcid.org/0000-0001-7549-9326)
- Andreas Schneeweiß (ORCID: https://orcid.org/0000-0002-2429-4512)
- Roberto Würth (ORCID: https://orcid.org/0000-0002-8156-6756)
- Paul Schwerd‐Kleine (ORCID: https://orcid.org/0009-0000-1328-9809)
- Peter Lichter (ORCID: https://orcid.org/0000-0002-2960-5279)
- Thilo Miersch (ORCID: https://orcid.org/0009-0008-7232-1408)
- Rebecca Weber (ORCID: https://orcid.org/0009-0008-8226-6019)
- Torsten Müller (ORCID: https://orcid.org/0009-0001-5498-4549)
- Beatrice Charlotte. Tröster (ORCID: https://orcid.org/0009-0000-3329-3135)
Institutions
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- National Center for Tumor Diseases (DE)
- Heidelberg University (US)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2026-10-28
- DOI
- https://doi.org/10.1158/2159-8290.cd-26-1312
- Primary Topic
- HER2/EGFR in Cancer Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00