Integrin alphavbeta3 Is a Master Regulator of Resistance to TKI-Induced Ferroptosis in HER2-Positive Breast Cancer
- Author(s)
- Nagpal, A; Needham, K; Lane, DJR; Ayton, S; Redvers, RP; John, M; Selistre-de-Araujo, HS; Denoyer, D; Pouliot, N;
- Details
- Publication Year 2023,Volume 15,Issue #4,Page 1216
- Journal Title
- Cancers
- Publication Type
- Research article
- 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 alphavbeta3 integrin is a critical mediator of resistance to TKI-induced ferroptosis. Our findings indicate that alphavbeta3 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 "alphavbeta3 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.
- Publisher
- MDPI
- Department(s)
- Laboratory Research
- PubMed ID
- 36831558
- Publisher's Version
- https://doi.org/10.3390/cancers15041216
- Open Access at Publisher's Site
https://doi.org/10.3390/cancers15041216- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2023-06-13 07:55:04
Last Modified: 2023-06-13 07:56:08