Targeting Integrins for Cancer Therapy - Disappointments and Opportunities.

Cecilia Bergonzini,Kim Kroese,Erik H J Danen,Annelien J M Zweemer

doi:10.3389/fcell.2022.863850

Abstract

Integrins mediate adhesive interactions between cells and their environment, including neighboring cells and extracellular matrix (ECM). These heterodimeric transmembrane receptors bind extracellular ligands with their globular head domains and connect to the cytoskeleton through multi-protein interactions at their cytoplasmic tails. Integrin containing cell–matrix adhesions are dynamic force-responsive protein complexes that allow bidirectional mechanical coupling of cells with their environment. This allows cells to sense and modulate tissue mechanics and regulates intracellular signaling impacting on cell faith, survival, proliferation, and differentiation programs. Dysregulation of these functions has been extensively reported in cancer and associated with tumor growth, invasion, angiogenesis, metastasis, and therapy resistance. This central role in multiple hallmarks of cancer and their localization on the cell surface makes integrins attractive targets for cancer therapy. However, despite a wealth of highly encouraging preclinical data, targeting integrin adhesion complexes in clinical trials has thus far failed to meet expectations. Contributing factors to therapeutic failure are 1) variable integrin expression, 2) redundancy in integrin function, 3) distinct roles of integrins at various disease stages, and 4) sequestering of therapeutics by integrin-containing tumor-derived extracellular vesicles. Despite disappointing clinical results, new promising approaches are being investigated that highlight the potential of integrins as targets or prognostic biomarkers. Improvement of therapeutic delivery at the tumor site via integrin binding ligands is emerging as another successful approach that may enhance both efficacy and safety of conventional therapeutics. In this review we provide an overview of recent encouraging preclinical findings, we discuss the apparent disagreement between preclinical and clinical results, and we consider new opportunities to exploit the potential of integrin adhesion complexes as targets for cancer therapy.

Highlights

Integrin StructureIntegrins represent a family of transmembrane adhesion receptors, facilitating the adhesive connection between cells and their surrounding extracellular matrix (ECM) or neighboring cells (Takada et al, 2007; Barczyk et al, 2009; Kadry and Calderwood, 2020)
The globular head domain creates a binding site for extracellular ligands while the short cytoplasmic tails interact with a cluster of associated proteins that connects to the cytoskeleton
In this review we focus on integrins as drug targets in cancer and discuss the apparent disagreement between preclinical and clinical results, we provide an overview of new encouraging preclinical findings and consider new opportunities to exploit the potential of integrin adhesion complexes in the effective treatment of cancer

Summary

INTRODUCTION

Integrins represent a family of transmembrane adhesion receptors, facilitating the adhesive connection between cells and their surrounding extracellular matrix (ECM) or neighboring cells (Takada et al, 2007; Barczyk et al, 2009; Kadry and Calderwood, 2020) They comprise a group of heterodimeric proteins generated by non-covalent association of an a- and a ß-subunit (Ginsberg, 2014). For the large family of β1 integrins, dual roles have been identified in growth versus metastasis, indicating that caution is warranted for their application as therapeutic targets (Ramirez et al, 2011; Moran-Jones et al, 2012; Truong et al, 2014; Moritz et al, 2021) Integrins such as αvβ, αvβ, and α5β1, are expressed on tumor cells but are induced on endothelial cells during the process of angiogenesis (Friedlander et al, 1995; Avraamides et al, 2008).

Result

Findings

CONCLUSIONS AND FUTURE PERSPECTIVES