TY - JOUR
T1 - Hypoxia attenuates trastuzumab uptake and trastuzumab-emtansine (T-DM1) cytotoxicity through redistribution of phosphorylated caveolin-1
AU - Chandran, Vineesh Indira
AU - Mansson, Ann Sofie
AU - Barbachowska, Magdalena
AU - Cerezo-Magana, Myriam
AU - Nodin, Bjorn
AU - Joshi, Bharat
AU - KoppaD.A., Neelima
AU - Saad, Ola M.
AU - Gluz, Oleg
AU - Isaksson, Karolin
AU - Borgquist, Signe
AU - Jirstrom, Karin
AU - Nabi, Ivan Robert
AU - Jernstrom, Helena
AU - Belting, Mattias
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
U2 - 10.1158/1541-7786.MCR-19-0856
DO - 10.1158/1541-7786.MCR-19-0856
M3 - Article
C2 - 31900313
AN - SCOPUS:85082931649
SN - 1541-7786
VL - 18
SP - 644
EP - 656
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 4
ER -