Abstract
PurposeTargeted 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.MethodsTo 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.ResultsTreatment 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.ConclusionTogether these data indicate a role for HO-1-induced autophagy in resistance to pan-HER family kinase inhibitors.
Highlights
HER2 is a member of the human epidermal growth factor receptor (EGFR) family which consists of four members (HER1, HER2, HER3 and HER4)
We have previously demonstrated that genetic loss of phosphatase and tensin homologue (PTEN) in HER2-driven mammary tumors confers resistance to the tyrosine kinase inhibitor sapatinib [13]
Modulation of heme oxygenase 1 (HO-1) expression has emerged as a potential therapeutic target for certain cardiovascular and neurodegenerative diseases where it provides a cytoprotective function [14]
Summary
HER2 is a member of the human epidermal growth factor receptor (EGFR) family which consists of four members (HER1, HER2, HER3 and HER4) The introduction of HER2-targeted therapies has had a major impact on the treatment of the disease, resistance remains a significant clinical problem. Both de novo and acquired resistance impact detrimentally on patient outcomes, reducing progression-free survival. Several mechanisms of resistance have been identified in preclinical models, but these have proven difficult to translate into clinical benefit [7,8,9].
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