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Nat Med. 2017 Oct;23(10):1167-1175. doi: 10.1038/nm.4401. Epub 2017 Sep 18.

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

Author information

Cancer Therapeutics Research Laboratory, National Cancer Centre Singapore, Singapore.
Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
Genome Institute of Singapore, Agency for Science, Technology &Research (A*STAR), Singapore.
Institute of Medical Biology, Agency for Science, Technology &Research (A*STAR), Singapore.
Department of Pathology, Singapore General Hospital, Singapore.
IMCB-NCC Singapore Oncogenome Program, Institute of Molecular and Cell Biology, Singapore.
Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore.
Laboratory of Clinical Pharmacology, National Cancer Centre Singapore, Singapore.
Office of Clinical Sciences, Duke-NUS Medical School, Singapore.
Division of Surgical Oncology, National Cancer Centre Singapore, Singapore.


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.

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