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<p>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<sub>2</sub> receptor (CB<sub>2</sub>R) in trastuzumab resistance. In human breast cancer samples, a decreased expression of HER2-CB<sub>2</sub>R heterodimers following neoadjuvant treatment, due to CB<sub>2</sub>R downregulation, was linked to poor long-term outcomes. Using various preclinical models, we demonstrate that CB<sub>2</sub>R drives trastuzumab resistance. Mechanistically, CB<sub>2</sub>R loss enabled cancer cells to evade antitumor IFN-γ signaling while promoting a shift from HER2-CB<sub>2</sub>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<sub>2</sub>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<sub>2</sub>R-selective cannabinoid therapies as potential strategies to overcome CB<sub>2</sub>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月11日

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  • Marta Seijo-Vila,
  • Sofía A. Balsinde,
  • Sandra Blasco-Benito,
  • Isabel Tundidor,
  • María Rubert-Hernández,
  • Ana Montero-Calle,
  • Rodrigo Barderas,
  • Laura E. Kilpatrick,
  • Simon Platt,
  • Noemi Karsai,
  • Isabel Philps,
  • Olga M. Antón,
  • Déborah Gómez-Domínguez,
  • Ignacio Pérez de Castro,
  • Carmen González-Lois,
  • Diego García-Fresnadillo,
  • Gala Silvestre-Egea,
  • Antonio J. Sánchez-López,
  • Esther Ramírez-Medina,
  • María Catalina Rivas Prieto,
  • Belén Almoguera Pérez-Cejuela,
  • Luis Manso,
  • Sandra Zazo,
  • Noemí López-Ejeda,
  • Francisco Palomino-Duque,
  • María Turienzo-Durán,
  • Nuria G. Martínez-Illescas,
  • María Salazar-Roa,
  • Sonia Castillo-Lluva,
  • Stephen J. Hill,
  • Manuel Guzmán,
  • Eduardo Pérez-Gómez,
  • Cristina Sánchez

摘要

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.