2026-08-22T00:40:11Zhttps://docta.ucm.es/rest/oai/request

oai:docta.ucm.es:20.500.14352/1387772026-07-22T00:31:35Zcom_20.500.14352_14col_20.500.14352_15

Cannabinoid CB2 receptor drives trastuzumab resistance and predicts durable anti-HER2 response Seijo Vila, Marta Balsinde, Sofía A. Blasco Benito, Sandra Tundidor, Isabel Rubert Hernández, María Montero Calle, Ana Barderas Manchado, Rodrigo Kilpatrick, Laura E. Platt, Simon Karsai, Noemi Philps, Isabel Antón Hurtado, Olga María Gómez Domínguez, Déborah Pérez de Castro, Ignacio González Lois, Carmen García Fresnadillo, Diego Silvestre Egea, Gala Sánchez López, Antonio J. Ramírez Medina, Esther Rivas Prieto, María Catalina Almoguera Pérez Cejuela, Belén Manso, Luis Zazo, Sandra López Ejeda, Noemí Palomino Duque, Francisco Turienzo Durán, María García Martínez-Illescas, Nuria Salazar Roa, María Castillo Lluva, Sonia Hill, Stephen J. Guzmán Pastor, Manuel Pérez Gómez, Eduardo Sánchez García, María Cristina 616-006 615.015 615.37 Oncología Farmacología (Medicina) Biología molecular (Biología) 3201.01 Oncología 2302.22 Farmacología Molecular 2302.21 Biología Molecular 3208.04 Lugar de Acción Activa, Receptores his study has been funded by Instituto de Salud Carlos III (grants PI17/00041, PI20/00590 and PI23/00765 to CS and EP-G; PI20CIII/00019 and PI23CIII/00027 to RB; and PI20CIII/00038 to IPC, all of them co-funded by the European Union); Medical Research Council UK (grant MR/W016176/1 to LEK and SJH); Spanish Ministry of Science, Innovation and Universities, the State Research Agency (grants PID2023-147678OB-I00 to IPC; PDI2021-1246320B-100 to SC-L; and CNS2022-135364 and PID2022-136508OA-I00 to MS-R, all supported with European Regional Development funds); UCM/Banco Santander (grants PR12/24-31549 to OMA and PR3/23-30841 to MS-R); Asociación Española Contra el Cáncer (Postdoctoral AECC 2023 POSTD234709BLAS to SB-B). 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 CB2 receptor (CB2R) in trastuzumab resistance. In human breast cancer samples, a decreased expression of HER2-CB2R heterodimers following neoadjuvant treatment, due to CB2R downregulation, was linked to poor long-term outcomes. Using various preclinical models, we demonstrate that CB2R drives trastuzumab resistance. Mechanistically, CB2R loss enabled cancer cells to evade antitumor IFN-γ signaling while promoting a shift from HER2-CB2R 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 CB2R 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-CB2R-selective cannabinoid therapies as potential strategies to overcome CB2R-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. Instituto de Salud Carlos III European Commission Medical Research Council (Great Britain) Ministerio de Ciencia e Innovación (España) Asociación Española Contra el Cáncer Universidad Complutense de Madrid Banco de Santander Depto. de Bioquímica y Biología Molecular Fac. de Ciencias Biológicas Fac. de Ciencias Químicas TRUE pub 2026-07-21T11:40:22Z 2026-07-21T11:40:22Z 2026-05 journal article VoR https://hdl.handle.net/20.500.14352/138777 0950-9232 10.1038/s41388-026-03814-9 1476-5594 eng info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2023-147678OB-I00/ES/LA VIA DE LOS GLUCOCORTICOIDES EN LA DISTROFIA MUSCULAR CONGENITA RELACIONADA CON LMNA: DESCIFRANDO MECANISMOS Y PROBANDO ESTRATEGIAS TERAPEUTICAS/ info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PDI2021-1246320B-100/ES info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-136508OA-I00/ES/BENEFICIOS TERAPEUTICOS DE LOS CANNABINOIDES COMO AGENTES DE DIFERENCIACION EN CANCER DE MAMA/ Seijo-Vila, M., Balsinde, S.A., Blasco-Benito, S. et al. Cannabinoid CB2 receptor drives trastuzumab resistance and predicts durable anti-HER2 response. Oncogene 45, 2436–2451 (2026). https://doi.org/10.1038/s41388-026-03814-9 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ open access application/pdf Springer Nature