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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 3/2020

Open Access 01-02-2020 | Breast Cancer | Preclinical study

HO-1 drives autophagy as a mechanism of resistance against HER2-targeted therapies

Authors: Natasha Tracey, Helen Creedon, Alain J. Kemp, Jayne Culley, Morwenna Muir, Teresa Klinowska, Valerie G. Brunton

Published in: Breast Cancer Research and Treatment | Issue 3/2020

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Abstract

Purpose

Targeted therapies have resulted in major advances in the treatment of HER2-positive breast cancers. Despite this, up to 70% of patients will develop resistance to treatment within 2 years and new strategies for targeting resistant disease are needed.

Methods

To identify potential resistance mechanisms, we used the mouse MMTV-NIC-PTEN+/− spontaneous model of HER2-positive breast cancer and the pan-HER family kinase inhibitor sapatinib. Vehicle and sapatinib-treated tumors were evaluated by immunohistochemistry and proteomic analysis. In vitro studies were carried out to define the role of heme oxygenase 1 (HO-1) and autophagy in resistance to sapatinib and lapatinib, another pan-HER family kinase inhibitor.

Results

Treatment of tumor-bearing MMTV-NIC-PTEN+/− mice with sapatinib resulted in delayed tumor progression and increased survival. However, tumors eventually progressed on treatment. Proteomic analysis identified proteins associated with cellular iron homeostasis as being upregulated in the sapatinib-treated tumors. This included HO-1 whose overexpression was confirmed by immunohistochemistry. Overexpression of HO-1 in HER2-expressing SKBR3 breast cancer cells resulted in reduced sensitivity to both pan-HER family kinase inhibitors sapatinib and lapatinib. This was associated with increased autophagy in the HO-1 over-expressing cells. Furthermore, increased autophagy was also seen in the sapatinib-treated tumors. Treatment with autophagy inhibitors was able to increase the sensitivity of the HO-1 over-expressing cells to both lapatinib and sapatinib.

Conclusion

Together these data indicate a role for HO-1-induced autophagy in resistance to pan-HER family kinase inhibitors.
Appendix
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Metadata
Title
HO-1 drives autophagy as a mechanism of resistance against HER2-targeted therapies
Authors
Natasha Tracey
Helen Creedon
Alain J. Kemp
Jayne Culley
Morwenna Muir
Teresa Klinowska
Valerie G. Brunton
Publication date
01-02-2020
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 3/2020
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-019-05489-1

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