Journal Article

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

Kwang, Xue Lin, Iyer, N Gopalakrishna, Chong, Fui Teen, Tan, Gek San, Lim, Tony K H, Sampath, Prabha, Lau, Dawn P, Lim, Wan Teck, Skanderup, Anders J, Leong, Hui Sun, Toh, Shen Yon, Tan, Daniel S W, Tan, Eng Huat, Zhang, Xiaoqian, DasGupta, Ramanuj, Sundaram, Gopinath M, Chowbay, Balram, Ang, Mei Kim, Chang, Mei Mei, Chua, Boon Tin

2017

Overview

A silent single-nucleotide variant (SNV) affecting the transcription of a long noncoding RNA (lncRNA EGFR-AS1) within the EGFR coding region alters the EGFR isoform ratio and modulates oncogene addiction and response to EGFR tyrosine kinase inhibitors in squamous-cell cancers. Proof-of-concept validation in patients supports the notion that this SNV and levels of the lncRNA could be used to predict response to therapy in a clinical setting. These results, together with findings by Bal et al ., uncover the functional role of noncoding RNAs in modulating the response to targeted therapies in cancer. Targeting EGFR is a validated approach in the treatment of squamous-cell cancers (SCCs), although there are no established biomarkers for predicting response. We have identified a synonymous mutation in EGFR , c.2361G>A (encoding p.Gln787Gln), in two patients with head and neck SCC (HNSCC) who were exceptional responders to gefitinib, and we showed in patient-derived cultures that the A/A genotype was associated with greater sensitivity to tyrosine kinase inhibitors (TKIs) as compared to the G/A and G/G genotypes. Remarkably, single-copy G>A nucleotide editing in isogenic models conferred a 70-fold increase in sensitivity due to decreased stability of the EGFR-AS1 long noncoding RNA (lncRNA). In the appropriate context, sensitivity could be recapitulated through EGFR-AS1 knockdown in vitro and in vivo , whereas overexpression was sufficient to induce resistance to TKIs. Reduced EGFR-AS1 levels shifted splicing toward EGFR isoform D, leading to ligand-mediated pathway activation. In co-clinical trials involving patients and patient-derived xenograft (PDX) models, tumor shrinkage was most pronounced in the context of the A/A genotype for EGFR-Q787Q, low expression of EGFR-AS1 and high expression of EGFR isoform D. Our study reveals how a 'silent' mutation influences the levels of a lncRNA, resulting in noncanonical EGFR addiction, and delineates a new predictive biomarker suite for response to EGFR TKIs.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13/1 / 13/106 / 13/89 / 13/95 / 14/32 / 42/41 / 631/337/384/2568 / 631/67/1059/602 / 631/67/1857 / 64/60 / 96/109 / 96/44 / Addictions / Adult / Aged / Aged, 80 and over / Biomarkers / Biomedicine / Cancer / Cancer Research / Carcinoma, Squamous Cell - drug therapy / Carcinoma, Squamous Cell - genetics / Care and treatment / Cell Proliferation / Cells / Clinical trials / Development and progression / Drug Resistance, Neoplasm - genetics / Epidermal growth factor / Epidermal growth factor receptors / ErbB Receptors - genetics / Esophageal Neoplasms - drug therapy / Esophageal Neoplasms - genetics / Esophageal Squamous Cell Carcinoma / Female / Gefitinib / Gene expression / Gene Knockdown Techniques / Genetic aspects / Genotypes / Head / Head and neck / Head and Neck Neoplasms - drug therapy / Head and Neck Neoplasms - genetics / Health aspects / Humans / In Vitro Techniques / Infectious Diseases / Male / Mathematical models / Medical research / Metabolic Diseases / Middle Aged / Molecular Medicine / Molecular Targeted Therapy / Mouth Neoplasms - drug therapy / Mouth Neoplasms - genetics / Mutation / Neurons / Neurosciences / Patients / Protein Kinase Inhibitors - therapeutic use / Protein-tyrosine kinase / Quinazolines - therapeutic use / Ribonucleic acid / RNA / RNA Isoforms / RNA Splicing / RNA, Long Noncoding - genetics / Sensitivity / Shrinkage / Splicing / Squamous cell carcinoma / Squamous Cell Carcinoma of Head and Neck / Tyrosine / Xenograft Model Antitumor Assays / Xenografts