Crosstalk Between ERα and Receptor Tyrosine Kinase Signalling and Implications for the Development of Anti-Endocrine Resistance

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2018 Jun 22

PMID 29925812

Citations 9

Authors

Rugaia Z Montaser

Helen M Coley

Affiliations

Soon will be listed here.

Abstract

Although anti-endocrine therapies have significantly advanced the treatment of breast cancer, they pose the problem of acquired drug resistance. The oestrogen receptor (ER)-expressing breast cancer cell lines MCF-7 and T47D alongside their in vitro derived resistant counterparts MCF-7-TR (tamoxifen-resistant) and T47D-FR (fulvestrant-resistant) showed dual resistance to fulvestrant and tamoxifen in the presence of upregulated HER1 and HER2 growth factor receptors. Our study demonstrated that tamoxifen resistance and fulvestrant resistance are associated with collateral sensitivity to the tyrosine kinase inhibitors (TKIs) lapatinib ( < 0.0001) and afatinib ( < 0.0001). Further, we found that over time, the TKIs reactivated ERα protein and/or mRNA in tamoxifen- and fulvestrant-resistant cells. Combinations of anti-endocrine agents with afatinib gave rise to significantly enhanced levels of apoptosis in both T47D-FR and MCF-7-TR in a synergistic manner versus additive effects of agents used singly. This was associated with p27 induction for anti-endocrine-resistant cells versus parental cells. Our data supports the use of combination treatment utilising dual HER1/2 inhibitors in breast cancer patients showing resistance to multiple anti-endocrine agents.

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