Cannabinoid CB2 receptor drives trastuzumab resistance and predicts durable anti-HER2 response

Year: 2026

Type: article

Abstract: Acquired or innate lack of response to standard HER2-targeted therapies remains a clinical issue in patients with HER2-positive breast cancer. Here, we investigated the role of the cannabinoid CB 2 receptor (CB 2 R) in trastuzumab resistance. In human breast cancer samples, a decreased expression of HER2-CB 2 R heterodimers following neoadjuvant treatment, due to CB 2 R downregulation, was linked to poor long-term outcomes. Using various preclinical models, we demonstrate that CB 2 R drives trastuzumab resistance. Mechanistically, CB 2 R loss enabled cancer cells to evade antitumor IFN-γ signaling while promoting a shift from HER2-CB 2 R to HER2-EGFR heterodimers, thus reducing dependence on HER2 and increasing reliance on EGFR-mediated pathways. Moreover, EGFR inhibition restored trastuzumab sensitivity. In summary, we reveal an unprecedented role for CB 2 R as a key regulator of oncogenic and immune signaling in response to anti-HER2 therapy and its potential as a predictive biomarker of therapeutic efficacy. We also propose dual HER2/EGFR targeting and non-CB 2 R-selective cannabinoid therapies as potential strategies to overcome CB 2 R-mediated trastuzumab resistance. Together, these findings position the endocannabinoid system as a pivotal and actionable node to elucidate, anticipate, and counteract resistance to HER2-targeted therapies.

Source: Oncogene

DOI: 10.1038/s41388-026-03814-9

Institutions: Universidad Complutense de Madrid, Research Institute Hospital 12 de Octubre, Municipal Institute for Medical Research, Hospital del Mar Research Institute, Instituto de Salud Carlos III, Unidad Funcional de Investigación de Enfermedades Crónicas, Centro de Investigación Biomédica en Red, Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable, University of Nottingham, University of Birmingham, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Instituto de Investigación de Enfermedades Raras, Hospital Universitario Puerta de Hierro Majadahonda, Hospital Universitario 12 De Octubre, Hospital Universitario Fundación Jiménez Díaz, Centro de Investigación Biomédica en Red de Cáncer, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Biomedical Research Networking Center on Neurodegenerative Diseases, Instituto Ramón y Cajal de Investigación Sanitaria

Language: English

Topic: HER2/EGFR in Cancer Research

Subfield: Oncology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $5,990

Funders: Banco Santander, Ministerio de Ciencia, Innovación y Universidades, European Commission, Medical Research Council, Instituto de Salud Carlos III

Awards: G1272900390, Los heterómeros HER2-CB2 como diana terapéutica y herramienta pronóstico/predictiva en cáncer de mama HER2 positivo, Potencial del sistema endocannabinoide como diana terapéutica y herramienta de cribado en cáncer de mama, G4212894969, El sistema endocannabinoide en el microambiente tumoral: papel en la progresión y respuesta a inmunoterapia en cáncer de mama, DESFRAGMENTACION DEL PAPEL PRINCIPAL EN CANCER COLORECTAL COMO BIOMARCADORES Y PARA INTERVENCION TERAPEUTICA DE PROTEINAS DE UNION A RNA, PROTEINAS OSCURAS Y PTMs, Exploiting a novel molecular toolkit to explore cell type specific adenosine receptor pharmacology and regulation at endogenous levels of expression., Identificación y validación de biomarcadores de cáncer colorectal involucrados en la diseminación del tumor, ESTUDIO DEL POTENCIAL DE LA TECNOLOGÍA CRISPR/CAS PARA EL TRATAMIENTO DE LA DISTROFIA MUSCULAR CONGÉNITA ASOCIADA A LMNA, G8895801233

OpenAlex ID: W7160860217