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

Chandran, Vineesh Indira LU ; Mansson, Ann Sofie LU ; Barbachowska, Magdalena LU ; Cerezo-Magana, Myriam LU orcid ; Nodin, Bjorn LU ; Joshi, Bharat ; KoppaD.A., Neelima ; Saad, Ola M. ; Gluz, Oleg and Isaksson, Karolin LU , et al. (2020) In Molecular Cancer Research 18(4). p.644-656
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Cancer Research
volume
18
issue
4
pages
13 pages
publisher
American Association for Cancer Research
external identifiers
  • pmid:31900313
  • scopus:85082931649
ISSN
1541-7786
DOI
10.1158/1541-7786.MCR-19-0856
language
English
LU publication?
yes
id
54dd7a43-4be5-4994-b59e-23f69ee9d566
date added to LUP
2020-04-29 12:18:02
date last changed
2024-04-03 05:24:16
@article{54dd7a43-4be5-4994-b59e-23f69ee9d566,
  abstract     = {{<p>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.</p>}},
  author       = {{Chandran, Vineesh Indira and Mansson, Ann Sofie and Barbachowska, Magdalena and Cerezo-Magana, Myriam and Nodin, Bjorn and Joshi, Bharat and KoppaD.A., Neelima and Saad, Ola M. and Gluz, Oleg and Isaksson, Karolin and Borgquist, Signe and Jirstrom, Karin and Nabi, Ivan Robert and Jernstrom, Helena and Belting, Mattias}},
  issn         = {{1541-7786}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{644--656}},
  publisher    = {{American Association for Cancer Research}},
  series       = {{Molecular Cancer Research}},
  title        = {{Hypoxia attenuates trastuzumab uptake and trastuzumab-emtansine (T-DM1) cytotoxicity through redistribution of phosphorylated caveolin-1}},
  url          = {{http://dx.doi.org/10.1158/1541-7786.MCR-19-0856}},
  doi          = {{10.1158/1541-7786.MCR-19-0856}},
  volume       = {{18}},
  year         = {{2020}},
}