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X-linked inhibitor of apoptosis protein mediates tumor cell resistance to antibody-dependent cellular cytotoxicity.

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Date
2016-01-28
Authors
Evans, MK
Sauer, SJ
Nath, S
Robinson, TJ
Morse, MA
Devi, GR
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Abstract
Inflammatory breast cancer (IBC) is the deadliest, distinct subtype of breast cancer. High expression of epidermal growth factor receptors [EGFR or human epidermal growth factor receptor 2 (HER2)] in IBC tumors has prompted trials of anti-EGFR/HER2 monoclonal antibodies to inhibit oncogenic signaling; however, de novo and acquired therapeutic resistance is common. Another critical function of these antibodies is to mediate antibody-dependent cellular cytotoxicity (ADCC), which enables immune effector cells to engage tumors and deliver granzymes, activating executioner caspases. We hypothesized that high expression of anti-apoptotic molecules in tumors would render them resistant to ADCC. Herein, we demonstrate that the most potent caspase inhibitor, X-linked inhibitor of apoptosis protein (XIAP), overexpressed in IBC, drives resistance to ADCC mediated by cetuximab (anti-EGFR) and trastuzumab (anti-HER2). Overexpression of XIAP in parental IBC cell lines enhances resistance to ADCC; conversely, targeted downregulation of XIAP in ADCC-resistant IBC cells renders them sensitive. As hypothesized, this ADCC resistance is in part a result of the ability of XIAP to inhibit caspase activity; however, we also unexpectedly found that resistance was dependent on XIAP-mediated, caspase-independent suppression of reactive oxygen species (ROS) accumulation, which otherwise occurs during ADCC. Transcriptome analysis supported these observations by revealing modulation of genes involved in immunosuppression and oxidative stress response in XIAP-overexpressing, ADCC-resistant cells. We conclude that XIAP is a critical modulator of ADCC responsiveness, operating through both caspase-dependent and -independent mechanisms. These results suggest that strategies targeting the effects of XIAP on caspase activation and ROS suppression have the potential to enhance the activity of monoclonal antibody-based immunotherapy.
Type
Journal article
Subject
Antibody-Dependent Cell Cytotoxicity
Apoptosis
Cell Line, Tumor
Cetuximab
Drug Resistance, Neoplasm
Female
Gene Knockdown Techniques
Humans
Immunotherapy
Inflammatory Breast Neoplasms
Killer Cells, Natural
NF-kappa B
Reactive Oxygen Species
Receptor, ErbB-2
Trastuzumab
X-Linked Inhibitor of Apoptosis Protein
Permalink
https://hdl.handle.net/10161/12402
Published Version (Please cite this version)
10.1038/cddis.2015.412
Publication Info
Evans, MK; Sauer, SJ; Nath, S; Robinson, TJ; Morse, MA; & Devi, GR (2016). X-linked inhibitor of apoptosis protein mediates tumor cell resistance to antibody-dependent cellular cytotoxicity. Cell Death Dis, 7. pp. e2073. 10.1038/cddis.2015.412. Retrieved from https://hdl.handle.net/10161/12402.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Devi

Gayathri R. Devi

Associate Professor in Surgery
Dr. Devi’s research interests include functional genomics, anti-cancer drug discovery and development, mechanisms of cancer cell signaling, tumor immunity and applications thereof for overcoming therapeutic resistance in cancer. The lab has established prostate, inflammatory breast cancer and ovarian cellular and tumor models.
Morse

Michael Aaron Morse

Professor of Medicine
We are studying the use of immune therapies to treat various cancers, including gastrointestinal, breast, and lung cancers and melanoma. These therapies include vaccines based on dendritic cells developed in our laboratory as well as vaccines based on peptides, viral vectors, and DNA plasmids. Our group is also a national leader in the development and use of laboratory assays for demonstrating immunologic responses to cancer vaccines. Finally, we are developing immunotherapies based on ado
Alphabetical list of authors with Scholars@Duke profiles.
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