Neuroendocrine Differentiation Mediates Escape from HER2-Targeted Therapy in Breast Cancer
Roberto Würth, Tasneem Cheytan, Paul Schwerd-Kleine, Ewgenija Gutjahr, Elisa Donato, Verena Thewes, Beatrice Charlotte. Tröster, Theresa Mulholland, Torsten Müller, Daria Doncevic, Laura L. Michel, Celina V. Wagner, Polina Kozyulina, Mario Hlevnjak, Marc Zapatka, Julia Bulkescher, Rebecca Weber, Sarah-Jane Neuberth, Vera Thiel, Thilo Miersch, Michael Scherer, Johannes Betge, Jeroen Krijgsveld, Carl Herrmann, Peter Lichter, Andreas Schneeweiss, Martin R. Sprick, Andreas TrumppAbstract
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.