Therapeutic targeting of HER2–CB2R heteromers in HER2-positive breast cancer

Although human epidermal growth factor receptor 2 (HER2)-targeted therapies have dramatically improved the clinical outcome of HER2-positive breast cancer patients, innate and acquired resistance remains an important clinical challenge. New therapeutic approaches and diagnostic tools for identification, stratification, and treatment of patients at higher risk of resistance and recurrence are therefore warranted. Here, we unveil a mechanism controlling the oncogenic activity of HER2: heteromerization with the cannabinoid receptor CB 2 R. We show that HER2 physically interacts with CB 2 R in breast cancer cells, and that the expression of these heteromers correlates with poor patient prognosis. The cannabinoid Δ 9 -tetrahydrocannabinol (THC) disrupts HER2–CB 2 R complexes by selectively binding to CB 2 R, which leads to ( i ) the inactivation of HER2 through disruption of HER2–HER2 homodimers, and ( ii ) the subsequent degradation of HER2 by the proteasome via the E3 ligase c-CBL. This in turn triggers antitumor responses in vitro and in vivo. Selective targeting of CB 2 R transmembrane region 5 mimicked THC effects. Together, these findings define HER2–CB 2 R heteromers as new potential targets for antitumor therapies and biomarkers with prognostic value in HER2-positive breast cancer.