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

Valerio Gelfo1, Francesca Pontis2, Martina Mazzeschi3

  • 1Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, Italy. valerio.gelfo2@unibo.it.

Journal of Clinical Medicine
|May 5, 2019
PubMed

Insights

Glucocorticoid Receptor (GR) activation can overcome cetuximab resistance in metastatic colorectal cancer (CRC) by modulating Epidermal Growth Factor Receptor (EGFR) feedback genes, suggesting a novel therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Crosstalk between Epidermal Growth Factor Receptor (EGFR) and Glucocorticoid Receptor (GR) influences cancer progression.
  • Cetuximab (CTX) resistance in metastatic colorectal cancer (CRC) is a significant clinical challenge.
  • EGFR feedback gene expression is implicated in the development of CTX resistance.

Purpose of the Study:

  • To investigate the role of EGFR positive and negative feedback genes in CTX resistance in CRC.
  • To evaluate the effect of GR modulation on these feedback genes in CTX-resistant CRC cells.
  • To explore the potential of combining GR modulation with EGFR inhibition for CRC treatment.

Main Methods:

  • Gene expression profiling of EGFR ligands (TGFA, HBEGF) and cytokines (IL-1B, IL-8).
  • Analysis of EGFR negative feedback genes (ERRFI1, DUSP1, LRIG3, LRIG1).
  • Assessment of gene expression changes in CTX-resistant cells following GR activation.
  • Correlation analysis in a xenopatient cohort stratified for CTX response.

Main Results:

  • EGFR positive feedback genes were upregulated, while negative feedback genes were downregulated in CTX-resistant CRC cells.
  • GR activation increased negative feedback genes (ERRFI1, DUSP1, LRIG1) and decreased EGFR activators (TGFA, IL-8).
  • Higher LRIG1 expression inversely correlated with CRC progression in patients treated with CTX.

Conclusions:

  • GR activation can restore EGFR negative feedback mechanisms, potentially overcoming CTX resistance.
  • Combining GR modulation with EGFR inhibition presents a promising strategy to halt CRC progression.
  • Targeting the EGFR-GR crosstalk offers a new therapeutic avenue for metastatic CRC.
Keywords:
DUSP1ERRFI1IL-1AIL-1BIL-8LRIG1cetuximab (CTX)colon cancerdexamethasoneepidermal growth factor receptorglucocorticoid receptormifepristonenegative feedback loopsnuclear receptorpositive feedback loopsresistance to monoclonal antibodies

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