Integrin αvβ3 Is a Master Regulator of Resistance to TKI-Induced Ferroptosis in HER2-Positive Breast Cancer

SIMPLE SUMMARY: Intrinsic or acquired resistance to clinically approved targeted therapies for breast cancer patients is a major cause of treatment failure. Our findings provide conclusive functional evidence that the cell adhesion receptor αvβ3 integrin is a critical mediator of resistance to Human Epidermal Growth Factor Receptor -2 (HER2)-targeting small molecule tyrosine kinase inhibitors (TKIs). We show that αvβ3 integrin contributes to the persistent activation of the AKT signalling pathway as well as to the re-wiring of the iron and antioxidant metabolism of the cells, thereby providing increased protection from an iron-dependent form of cell death called ferroptosis. Importantly, we demonstrate that genetic manipulation or therapeutic targeting of this receptor provides a novel strategy to reverse the resistance to TKI-induced ferroptosis in mouse and human HER2-positive breast cancer cells. We propose that the increased dependency on αvβ3 integrin signalling in TKI-resistant cells represents an Achilles’ heel that can be targeted pharmacologically to improve patient outcomes. ABSTRACT: Human epidermal growth factor receptor-2 (HER2)-targeting therapies provide clinical benefits for patients with HER2-positive breast cancer. However, the resistance to monotherapies invariably develops and leads to disease relapse and treatment failure. Previous studies have demonstrated a link between the potency of HER2-targeting tyrosine kinase inhibitors (TKIs) and their ability to induce an iron-dependent form of cell death called ferroptosis. The aim of this study was to understand the mechanisms of resistance to TKI-induced ferroptosis and identify novel approaches to overcome treatment resistance. We used mouse and human HER2-positive models of acquired TKI resistance to demonstrate an intimate link between the resistance to TKIs and to ferroptosis and present the first evidence that the cell adhesion receptor αvβ3 integrin is a critical mediator of resistance to TKI-induced ferroptosis. Our findings indicate that αvβ3 integrin-mediated resistance is associated with the re-wiring of the iron/antioxidant metabolism and persistent activation of AKT signalling. Moreover, using gene manipulation approaches and pharmacological inhibitors, we show that this “αvβ3 integrin addiction” can be targeted to reverse TKI resistance. Collectively, these findings provide critical insights into new therapeutic strategies to improve the treatment of advanced HER2-positive breast cancer patients.