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 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.
['Tracey|Natasha|N|', 'Creedon|Helen|H|', 'Kemp|Alain J|AJ|', 'Culley|Jayne|J|', 'Muir|Morwenna|M|', 'Klinowska|Teresa|T|', 'Brunton|Valerie G|VG|http://orcid.org/0000-0002-7778-8794']
D000818:Animals D000970:Antineoplastic Agents D001343:Autophagy D001943:Breast Neoplasms D045744:Cell Line, Tumor D004353:Drug Evaluation, Preclinical D019008:Drug Resistance, Neoplasm D005260:Female D051547:Heme Oxygenase-1 D006801:Humans D000077341:Lapatinib D008565:Membrane Proteins D051379:Mice D008822:Mice, Transgenic D058990:Molecular Targeted Therapy D047428:Protein Kinase Inhibitors D011799:Quinazolines D018719:Receptor, ErbB-2
HO-1 Autophagy Resistance Breast cancer HER2