Integrin v3 Is a Master Regulator of Resistance to TKI-Induced Ferroptosis in HER2-Positive Breast Cancer

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 alpha v beta 3 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 alpha v beta 3 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 alpha v beta 3 integrin signalling in TKI-resistant cells represents an Achilles' heel that can be targeted pharmacologically to improve patient outcomes.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 alpha v beta 3 integrin is a critical mediator of resistance to TKI-induced ferroptosis. Our findings indicate that alpha v beta 3 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 "alpha v beta 3 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.