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

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 two 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 hemoxygenase 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.