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

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.