The EGFR-AS1 Long Noncoding RNA Modulates EGFR TKI Sensitivity

EGFR inhibitors have achieved clinical success in a proportion of patients with head and neck squamous-cell cancers (HNSCC), but predictive biomarkers are needed to identify patients who will benefit. In a phase II clinical trial, two patients who had exceptional responses to the EGFR inhibitor gefitinib were found to have a synonymous mutation in EGFR (c.2361G>A), prompting Tan and colleagues to investigate the effects of this mutation on sensitivity to EGFR tyrosine kinase inhibitors (TKI). Six primary HNSCC cultures were treated with a EGFR TKIs, and the two cell lines with the EGFR A/A genotype exhibited sensitivity, whereas the G/A or G/G cells were resistant. Single-nucleotide editing to the A/A genotype was sufficient to reverse resistance to EGFR TKIs. The EGFR SNP was in a transcribed region that encodes the lncRNA EGFR-AS1, and the A/A genotype was associated with reduced stability of EGFR-AS1. In G/A or G/G patient-derived xenografts (PDX) expressing high levels of EGFR-AS1, depletion of EGFR-AS1 through locked nucleic acid antisense oligonucleotides suppressed tumor growth, indicating that EGFR-AS1 drives EGFR addiction. EGFR has four known isoforms (A–D), and EGFR-AS1 promoted their differential expression, with an increase in the isoform A:isoform D ratio. EGFR-AS1 depletion increased levels of isoform D, and was associated with increased EGFR TKI sensitivity. Further, isoform D knockdown rendered A/A genotype cells that were sensitive to gefitinib more resistant. PDXs from two patients with the A/A genotype exhibited tumor regression in response to EGFR TKIs, and based on these findings the patients were treated with EGFR TKIs (gefitinib or erlotinib). The first patient experienced regression of metastatic lesions and serum tumor markers, and the second patient had tumor shrinkage. Collectively, these findings uncover the mechanism by which synonymous EGFR mutation confers sensitivity to TKIs, and suggest the possibility for EGFR-AS1 or the EGFR isoform D:isoform A ratio as biomarkers of response for EGFR TKIs.

Tan DS, Chong FT, Leong HS, Toh SY, Lau DP, Kwang XL, et al. Long noncoding RNA EGFR-AS1 mediates epidermal growth factor receptor addiction and modulates treatment response in squamous cell carcinoma. Nat Med 2017 Sep 18 [Epub ahead of print].

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