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

Chandran, Vineesh Indira (author)
Lund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine
Mansson, Ann Sofie (author)
Lund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine
Barbachowska, Magdalena (author)
Lund University,Lunds universitet,Urologisk cancerforskning, Malmö,Forskargrupper vid Lunds universitet,Urological cancer, Malmö,Lund University Research Groups
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Cerezo-Magana, Myriam (author)
Lund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments
Nodin, Bjorn (author)
Lund University,Lunds universitet,Terapeutisk patologi,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Therapeutic pathology,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments
Joshi, Bharat (author)
Univ British Columbia, Dept Cellular & Physiol Sci, Inst Life Sci, Vancouver, BC, Canada.,University of British Columbia
Koppada, Neelima (author)
Genentech Inc, BioAnalyt Sci ADT, GRED, San Francisco, CA USA.
Saad, Ola M. (author)
Genentech Inc, BioAnalyt Sci ADT, GRED, San Francisco, CA USA.
Gluz, Oleg (author)
West German Study Grp, Monchengladbach, Germany.,West German Study Group GmbH
Isaksson, Karolin (author)
Lund University,Lunds universitet,Kirurgi, Lund,Sektion V,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Surgery (Lund),Section V,Department of Clinical Sciences, Lund,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments
Borgquist, Signe (author)
Lund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Aarhus University
Jirstrom, Karin (author)
Lund University,Lunds universitet,Terapeutisk patologi,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Therapeutic pathology,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments
Nabi, Ivan Robert (author)
Univ British Columbia, Dept Cellular & Physiol Sci, Inst Life Sci, Vancouver, BC, Canada.,University of British Columbia
Jernstrom, Helena (author)
Lund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments
Belting, Mattias (author)
Uppsala University,Lund University,Lunds universitet,Uppsala universitet,Neuroonkologi,Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiophys, Lund, Sweden,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Skåne University Hospital
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 (creator_code:org_t)
2020
2020
English.
In: Molecular Cancer Research. - 1541-7786 .- 1557-3125. ; 18:4, s. 644-656
Related links:
http://dx.doi.org/10... (free)
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https://urn.kb.se/re...
https://doi.org/10.1...
https://lup.lub.lu.s...
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

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