Hypoxia attenuates trastuzumab uptake and trastuzumab-emtansine (T-DM1) cytotoxicity through redistribution of phosphorylated caveolin-1

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  • Vineesh Indira Chandran, Lunds Universitet
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  • Ann Sofie Mansson, Lunds Universitet
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  • Magdalena Barbachowska, Lunds Universitet
  • ,
  • Myriam Cerezo-Magana, Lunds Universitet
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  • Bjorn Nodin, Lunds Universitet
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  • Bharat Joshi, The University of British Columbia
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  • Neelima KoppaD.A., Oncology Biomarker Development
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  • Ola M. Saad, Oncology Biomarker Development
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  • Oleg Gluz, West German Study Group
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  • Karolin Isaksson, Lunds Universitet
  • ,
  • Signe Borgquist
  • Karin Jirstrom, Lunds Universitet
  • ,
  • Ivan Robert Nabi, The University of British Columbia
  • ,
  • Helena Jernstrom, Lunds Universitet
  • ,
  • Mattias Belting, Lunds Universitet, Lund University, Uppsala University

The antibody drug conjugate trastuzumab-emtansine (T-DM1) offers an additional treatment option for patients with HER2-amplified tumors. However, primary and acquired resistance is a limiting factor in a significant subset of patients. Hypoxia, a hallmark of cancer, regulates the trafficking of several receptor proteins with potential implications for tumor targeting. Here, we have investigated how hypoxic conditions may regulate T-DM1 treatment efficacy in breast cancer. The therapeutic effect of T-DM1 and its metabolites was evaluated in conjunction with biochemical, flow cytometry, and high-resolution imaging studies to elucidate the functional and mechanistic aspects of hypoxic regulation. HER2 and caveolin-1 expression was investigated in a well-Annotated breast cancer cohort.Wefind that hypoxia fosters relative resistance to T-DM1 in HER2 cells (SKBR3 and BT474). This effect was not a result of deregulated HER2 expression or resistance to emtansine and its metabolites. Instead, we show that hypoxia-induced translocation of caveolin-1 from cytoplasmic vesicles to the plasma membrane contributes to deficient trastuzumab internalization and T-DM1 chemosensitivity. Caveolin-1 depletion mimicked the hypoxic situation, indicating that vesicular caveolin-1 is indispensable for trastuzumab uptake and T-DM1 cytotoxicity. In vitro studies suggested that HER2 and caveolin-1 are not coregulated, which was supported by IHC analysis in patient tumors. We find that phosphorylation-deficient caveolin-1 inhibits trastuzumab internalization and T-DM1 cytotoxicity, suggesting a specific role for caveolin-1 phosphorylation in HER2 trafficking.

OriginalsprogEngelsk
TidsskriftMolecular Cancer Research
Vol/bind18
Nummer4
Sider (fra-til)644-656
Antal sider13
ISSN1541-7786
DOI
StatusUdgivet - 2020

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