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

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.

Temporal Modulation of HER2 Membrane Availability Increases Pertuzumab Uptake and Pretargeted Molecular Imaging of Gastric Tumors

“…Temporal modulation of CAV1 with the cholesterol-lowering drug lovastatin increases HER2 availability at the cell membrane to enhance the binding of trastuzumab to gastric cancer cells (27). Our previous work showed an increase in HER2 half-life at the cell membrane of NCI-N87 gastric cancer cells.…”

“…However, clinical studies have reported that 89 Zrlabeled antibodies do not always accumulate in HER2-positive tumors (25). Immunohistochemical staining of gastric tumors reveals nonuniform membrane expression of HER2 (15), which contributes to low accumulation of antibodies in these tumors (18,26,27). Moreover, endocytic trafficking mediates HER2 internalization and further reduces the availability of HER2 at the cell membrane, preventing binding with antibodies such as trastuzumab and pertuzumab and dampening their therapeutic efficacy (27)(28)(29)(30).…”

“…Caveolin-1 (CAV1), a protein present in cholesterol-rich structures at the cell membrane, mediates HER2 internalization and reduces HER2 availability at the cell membrane for binding with trastuzumab (27,35,36). We have previously shown that temporal modulation of CAV1 protein with the cholesterol-lowering drug lovastatin improved HER2 stability at the cell membrane and increased and accelerated tumoral uptake of 89 Zr-labeled trastuzumab.…”

Hypoxia Attenuates Trastuzumab Uptake and Trastuzumab-Emtansine (T-DM1) Cytotoxicity through Redistribution of Phosphorylated Caveolin-1

“…Indeed, previous studies have demonstrated that HER2 is localized to cholesterolrich membrane raft regions where it may colocalize with GM1 (50) as well as CAV1 (51). Recent studies by Pereira and colleagues (52) suggested an inverse relationship between HER2 and CAV1 protein expression in a large collection of cancer cell lines and in examples of human gastric tumor specimens. In the present study, we were, however, unable to find a significant association between CAV1 expression and HER2 status in vitro as well as in a large, populationbased breast cancer cohort.…”

“…According to this scenario, the most obvious strategy would be to alleviate the hypoxic situation by, for example, tumor vessel normalization or actions that normalize CAV1 localization to allow more efficient targeting also of hypoxic tumor regions and potentially other niches distinguished by CAV1 clustering at the cell periphery. Interestingly, in models of gastric, bladder, and breast cancer, increased HER2 cell surface availability and improved trastuzumab therapy by disrupting CAV1-mediated HER2 internalization using the cholesterol lowering drug lovastatin were demonstrated (52). In the case of T-DM1, however, one would like to achieve the opposite effect, i.e., increased membrane cholesterol loading and CAV1-mediated HER2 internalization.…”