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Caveolin-1 mediates cellular distribution of HER2 and affects trastuzumab binding and therapeutic efficacy

Author

Listed:
  • Patrícia M. R. Pereira

    (Memorial Sloan Kettering Cancer Center)

  • Sai Kiran Sharma

    (Memorial Sloan Kettering Cancer Center)

  • Lukas M. Carter

    (Memorial Sloan Kettering Cancer Center)

  • Kimberly J. Edwards

    (Memorial Sloan Kettering Cancer Center)

  • Jacob Pourat

    (Memorial Sloan Kettering Cancer Center)

  • Ashwin Ragupathi

    (Memorial Sloan Kettering Cancer Center)

  • Yelena Y. Janjigian

    (Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College)

  • Jeremy C. Durack

    (Memorial Sloan Kettering Cancer Center
    Weill Cornell Medical College)

  • Jason S. Lewis

    (Memorial Sloan Kettering Cancer Center
    Weill Cornell Medical College
    Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center
    Weill Cornell Medical College)

Abstract

Human epidermal growth factor receptor 2 (HER2) gene amplification and/or protein overexpression in tumors is a prerequisite for initiation of trastuzumab therapy. Although HER2 is a cell membrane receptor, differential rates of endocytosis and recycling engender a dynamic surface pool of HER2. Since trastuzumab must bind to the extracellular domain of HER2, a depressed HER2 surface pool hinders binding. Using in vivo biological models and cultures of fresh human tumors, we find that the caveolin-1 (CAV1) protein is involved in HER2 cell membrane dynamics within the context of receptor endocytosis. The translational significance of this finding is highlighted by our observation that temporal CAV1 depletion with lovastatin increases HER2 half-life and availability at the cell membrane resulting in improved trastuzumab binding and therapy against HER2-positive tumors. These data show the important role that CAV1 plays in the effectiveness of trastuzumab to target HER2-positive tumors.

Suggested Citation

  • Patrícia M. R. Pereira & Sai Kiran Sharma & Lukas M. Carter & Kimberly J. Edwards & Jacob Pourat & Ashwin Ragupathi & Yelena Y. Janjigian & Jeremy C. Durack & Jason S. Lewis, 2018. "Caveolin-1 mediates cellular distribution of HER2 and affects trastuzumab binding and therapeutic efficacy," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07608-w
    DOI: 10.1038/s41467-018-07608-w
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