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

Patrícia M. R. Pereira, Sai Kiran Sharma, Lukas M. Carter, Kimberly J. Edwards, Jacob Pourat, Ashwin Ragupathi, Yelena Y. Janjigian, Jeremy C. Durack and Jason S. Lewis ()
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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
Jason S. Lewis: Memorial Sloan Kettering Cancer Center

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07608-w

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