Glucocorticoid Receptor Modulates EGFR Feedback upon Acquisition of Resistance to Monoclonal Antibodies.

Maria Mazzarini,Gabriele D’Uva,Michela Sgarzi,Valerio Gelfo,Martina Mazzeschi,Francesca Pontis,Mattia Lauriola,Rossella Solmi

doi:10.3390/jcm8050600

Abstract

Evidences of a crosstalk between Epidermal Growth Factor Receptor (EGFR) and Glucocorticoid Receptor (GR) has been reported, ranging from the modulation of receptor levels or GR mediated transcriptional repression of EGFR target genes, with modifications of epigenetic markers. The present study focuses on the involvement of EGFR positive and negative feedback genes in the establishment of cetuximab (CTX) resistance in metastatic Colorectal Cancer (CRC) patients. We evaluated the expression profile of the EGFR ligands TGFA and HBEGF, along with the pro-inflammatory cytokines IL-1B and IL-8, which were previously reported to be negatively associated with monoclonal antibody response, both in mice and patient specimens. Among EGFR negative feedback loops, we focused on ERRFI1, DUSP1, LRIG3, and LRIG1. We observed that EGFR positive feedback genes are increased in CTX-resistant cells, whereas negative feedback genes are reduced. Next, we tested the expression of these genes in CTX-resistant cells upon GR modulation. We unveiled that GR activation leads to an increase in ERRFI1, DUSP1, and LRIG1, which were shown to restrict EGFR activity, along with a decrease in the EGFR activators (TGFA and IL-8). Finally, in a cohort of xenopatients, stratified for response to cetuximab, we observed an inverse association between the expression level of LRIG1 and CRC progression upon CTX treatment. Our model implies that combining GR modulation to EGFR inhibition may yield an effective treatment strategy in halting cancer progression.

Highlights

Growth factors acting through receptor tyrosine kinases (RTKs) of ERBB family, along with steroid hormones acting through nuclear receptors (NRs), are critical signaling mediators of multiple cellular processes, including cell proliferation, survival, inflammation, differentiation, metabolism and migration [1]
We previously reported that a panel of inflammatory cytokines, including IL-1A, IL-1B, and IL-8, induced by epidermal growth factor (EGF) receptor (EGFR) activation, is associated with impaired therapeutic efficacy in a cohort of xenopatients treated with CTX [21], and that patients unresponsive to CTX displayed higher levels of IL-1 receptor 1 (IL-1R1) [22]
Among positive EGFR feedback regulators, we evaluated the expression profile of the EGFR ligands TGFA and HBEGF, which were previously found to be involved in CTX resistance [23,24], as well as the pro-inflammatory cytokines IL-1B and IL-8, which were negatively associated with monoclonal antibody response in xenopatients mice and patient specimens [21,25]

Summary

Introduction

Growth factors acting through receptor tyrosine kinases (RTKs) of ERBB family, along with steroid hormones acting through nuclear receptors (NRs), are critical signaling mediators of multiple cellular processes, including cell proliferation, survival, inflammation, differentiation, metabolism and migration [1]. The activation of glucocorticoid receptor (GR) by the glucocorticoids, which belong to the steroid hormone family, controls cell proliferation during lobulo-alveolar development of the mammary gland [3] and promotes breast cancer metastasis [4]. ERBB-induced signalling has been proven to directly repress the expression of sex hormones (androgen and estrogen) receptors [6]. ERBB signaling can indirectly regulate glucocorticoid receptor expression e.g., through the Notch pathway in leukemic cells [7,8], or through the tyrosine kinase cKIT in human erythroblasts [9]. We delineated a robust regulation of EGFR signalling by GR activation, involving both a massive transcriptional repression of EGFR positive feedback loops and simultaneous production of the negative ones [5,12]

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Results

Conclusion