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

Vineesh Indira Chandran, Ann Sofie Mansson, Magdalena Barbachowska, Myriam Cerezo-Magana, Bjorn Nodin, Bharat Joshi, Neelima KoppaD.A., Ola M. Saad, Oleg Gluz, Karolin Isaksson, Signe Borgquist, Karin Jirstrom, Ivan Robert Nabi, Helena Jernstrom, Mattias Belting

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)644-656
Number of pages13
JournalMolecular Cancer Research
Issue number4
Publication statusPublished - 2020

Subject classification (UKÄ)

  • Cancer and Oncology


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