Long noncoding RNA EGFR-AS1 mediates epidermal growth factor receptor addiction and modulates treatment response in...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Epidermal Growth Factor Receptor (EGFR) targeting is a key treatment for squamous-cell cancers (SCCs).
• Predictive biomarkers for EGFR-tyrosine kinase inhibitor (TKI) response in SCCs are lacking.
• A synonymous EGFR mutation (c.2361G>A, p.Gln787Gln) was observed in exceptional responders.

Purpose of the Study:

• To investigate the functional role of the synonymous EGFR c.2361G>A mutation.
• To identify biomarkers predicting response to EGFR TKIs in head and neck SCC (HNSCC).
• To elucidate the mechanism linking the mutation, long noncoding RNA, and TKI sensitivity.

Main Methods:

• Analysis of patient-derived cultures and isogenic models with different EGFR genotypes.
• Assessment of EGFR-AS1 long noncoding RNA (lncRNA) stability and expression.
• Evaluation of EGFR isoform D splicing and pathway activation.
• Co-clinical trials using patient-derived xenograft (PDX) models.

Main Results:

• The EGFR c.2361G>A mutation (A/A genotype) conferred significantly greater sensitivity to TKIs compared to G/A and G/G genotypes.
• The G>A nucleotide editing led to a 70-fold increase in TKI sensitivity by decreasing EGFR-AS1 lncRNA stability.
• EGFR-AS1 knockdown mimicked sensitivity, while overexpression induced resistance.
• Reduced EGFR-AS1 shifted splicing to EGFR isoform D, activating the EGFR pathway.
• Tumor shrinkage in co-clinical trials correlated with A/A genotype, low EGFR-AS1, and high EGFR isoform D expression.

Conclusions:

• The synonymous EGFR c.2361G>A mutation influences EGFR-AS1 lncRNA levels, leading to noncanonical EGFR pathway activation and TKI sensitivity.
• EGFR-AS1 lncRNA and EGFR isoform D expression serve as a novel predictive biomarker suite for EGFR TKI response in HNSCC.
• This discovery offers a new strategy for personalized treatment of squamous-cell cancers.