Therapeutic targeting of HER2–CB ₂ R heteromers in HER2-positive breast cancer

Abstract

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 CB2R. We show that HER2 physically interacts with CB2R in breast cancer cells, and that the expression of these heteromers correlates with poor patient prognosis. The cannabinoid Δ9-tetrahydrocannabinol (THC) disrupts HER2–CB2R complexes by selectively binding to CB2R, 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 CB2R transmembrane region 5 mimicked THC effects. Together, these findings define HER2–CB2R heteromers as new potential targets for antitumor therapies and biomarkers with prognostic value in HER2-positive breast cancer.

Cannabinoid Combination Induces Cytoplasmic Vacuolation in MCF-7 Breast Cancer Cells

“…This could explain why the two cannabinoid combinations containing THC had the lowest IC values amongst the combinations tested ( Table 2 ). In addition, the binding of cannabinoids to the CB 2 receptor disrupts the HER2/CB 2 heterodimer formation, inhibiting proliferation via the PI3K/Akt pathway [ 41 ]. Since the C6 combination comprises four cannabinoids that can all bind to the CB2 receptor [ 42 ], their anti-proliferative effects in the MCF-7 cells would be amplified when cannabinoids are combined.…”

The Endocannabinoid System: A Target for Cancer Treatment

“…Lastly, Blasco-Benito et al observed that HER2 interacts with CB2 receptors in breast cancer cells and the expression of these heteromers correlates with poor patient prognosis. The cannabinoid ∆9-THC disrupted HER2-CB2R complexes by selectively binding to CB2R, which led to the inactivation and degradation of HER2 through disruption of HER2-HER2 homodimers promoting antitumoral responses both in vitro and in vivo, which may constitute a new strategy to treat HER2+ breast tumors [84].…”

Editorial: The Canonical and Non-Canonical Endocannabinoid System as a Target in Cancer and Acute and Chronic Pain

“…High CB1R expression correlates with poor prognosis in different type of cancers including prostate, pancreatic, colorectal, and ovarian cancer (Michalski et al, 2008;Cipriano et al, 2013;Jung et al, 2013;Messalli et al, 2014); while high CB2R expression correlated to poor prognosis in HER2positive breast cancer (Blasco-Benito et al, 2019). Endocannabinoids such as AEA and 2-AG were found upregulated in different tumors (colorectal carcinomas) compared to healthy subjects (Pyszniak et al, 2016).Despite these changes there have been variable mechanisms suggested for these endocannabinoids in terms of their antitumorigenic activity.…”