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

Proc Natl Acad Sci U S A. 2019 Feb 26;116(9):3863-3872. doi: 10.1073/pnas.1815034116. Epub 2019 Feb 7.

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.

Keywords: CB2R; HER2; breast cancer; cannabinoids; receptor heteromers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / cerebrospinal fluid*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Dronabinol / pharmacology
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Molecular Targeted Therapy*
  • Neoplasm Recurrence, Local / drug therapy
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / pathology
  • Protein Multimerization / drug effects
  • Proto-Oncogene Proteins c-cbl / genetics
  • Receptor, Cannabinoid, CB2 / chemistry
  • Receptor, Cannabinoid, CB2 / genetics*
  • Receptor, ErbB-2 / chemistry
  • Receptor, ErbB-2 / genetics*
  • Signal Transduction

Substances

  • Receptor, Cannabinoid, CB2
  • Dronabinol
  • Proto-Oncogene Proteins c-cbl
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • CBL protein, human