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

Marta Seijo-Vila1,2, Sofía A Balsinde1,2, Sandra Blasco-Benito3

  • 1Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, Complutense University of Madrid, Madrid, Spain.

Oncogene
|May 11, 2026
PubMed

Insights

Cannabinoid receptor 2 (CB2R) downregulation drives trastuzumab resistance in HER2-positive breast cancer by altering signaling pathways. Targeting CB2R or EGFR may overcome resistance and improve patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Resistance to HER2-targeted therapies like trastuzumab is a significant clinical challenge in HER2-positive breast cancer.
  • The role of the cannabinoid CB2 receptor (CB2R) in mediating this resistance is not well understood.

Purpose of the Study:

  • To investigate the role of CB2R in trastuzumab resistance in HER2-positive breast cancer.
  • To elucidate the underlying mechanisms of CB2R-mediated resistance.
  • To identify potential therapeutic strategies to overcome resistance.

Main Methods:

  • Analysis of human breast cancer samples for HER2-CB2R heterodimer expression.
  • Preclinical models to study CB2R function in trastuzumab resistance.
  • Investigation of signaling pathways including IFN-γ and EGFR.

Main Results:

  • Decreased HER2-CB2R heterodimers and CB2R downregulation correlate with poor outcomes in patients.
  • CB2R loss promotes trastuzumab resistance by enabling evasion of IFN-γ signaling.
  • CB2R loss induces a shift to HER2-EGFR heterodimers, increasing EGFR pathway reliance.
  • EGFR inhibition restores sensitivity to trastuzumab.

Conclusions:

  • CB2R is a key regulator of oncogenic and immune signaling in response to anti-HER2 therapy.
  • CB2R can serve as a predictive biomarker for trastuzumab efficacy.
  • Dual HER2/EGFR targeting and non-CB2R-selective cannabinoid therapies are potential strategies to overcome resistance.

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