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

Abstract：

: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.

journal_name

Nat Med

journal_title

Nature medicine

authors

Tan DSW,Chong FT,Leong HS,Toh SY,Lau DP,Kwang XL,Zhang X,Sundaram GM,Tan GS,Chang MM,Chua BT,Lim WT,Tan EH,Ang MK,Lim TKH,Sampath P,Chowbay B,Skanderup AJ,DasGupta R,Iyer NG

doi

10.1038/nm.4401

subject

Has Abstract

pub_date

2017-10-01 00:00:00

pages

1167-1175

issue

10

eissn

1078-8956

issn

1546-170X

pii

nm.4401

journal_volume

23

pub_type

杂志文章

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