Integrin-mediated resistance to epidermal growth factor receptor-targeted therapy: an inflammatory situation.

Wells S Brown,Michael K Wendt

doi:10.1186/s13058-014-0448-0

Abstract

Targeting the function of epidermal growth factor receptor (EGFR) has failed as an effective clinical option for breast cancer. Understanding the drivers of inherent resistance has been a challenge. One possible mechanism is the acquisition of stem-like properties through the process of epithelial-mesenchymal transition. A recent study by Seguin and colleagues adds to our understanding of this process by demonstrating a functional role for unligated αvβ3 integrin in mediating a stem-like phenotype and facilitating resistance to EGFR-targeted therapy via enhanced downstream coupling to a KRAS:RalB:NF-κB pathway. Importantly, the identified mechanism may reveal a possible strategy for sensitizing breast cancer cells to EGFR-targeted therapies.

Highlights

Expression of epidermal growth factor receptor (EGFR) serves as a robust marker for the basal-like subtype of breast cancer (BC) and a biomarker for decreased survival times of BC patients [1,2]
Use of the nonadherent tumor sphere assay was the first indication that the role of β3 integrin in modulating tumor initiating capacity was independent of its role in cell adhesion
The authors demonstrate that β3 integrin is necessary and sufficient to impart growth resistance to the EGFR inhibitor erlotinib

Summary

Introduction

Expression of epidermal growth factor receptor (EGFR) serves as a robust marker for the basal-like subtype of breast cancer (BC) and a biomarker for decreased survival times of BC patients [1,2]. Aberrant expression of β3 integrin is strongly related to epithelialmesenchymal transition [9], a process involved in several aspects of tumor metastasis [10], generation of a stemlike state [11] and resistance to EGFR-targeted therapies [12]. The functional role of β3 integrin in mediating a stem-like state and resistance to EGFR-targeted therapies has remained undefined.

Results

Conclusion