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.

中文翻译：

---

长的非编码RNA EGFR-AS1介导表皮生长因子受体成瘾并调节鳞状细胞癌的治疗反应。

靶向EGFR是治疗鳞状细胞癌（SCC）的有效方法，尽管尚无可预测反应的生物标志物。我们在两名对吉非替尼有特殊反应的头颈SCC（HNSCC）患者中鉴定出EGFR的同义突变c.2361G> A（编码p.Gln787Gln），并且在患者衍生的培养物中证明了A与G / A和G / G基因型相比，/ A基因型对酪氨酸激酶抑制剂（TKIs）的敏感性更高。值得注意的是，由于EGFR-AS1长非编码RNA（lncRNA）的稳定性降低，在等基因模型中的单拷贝G> A核苷酸编辑使敏感性提高了70倍。在适当的情况下，可以通过体内外的EGFR-AS1抑制来概括敏感性，而过表达足以诱导对TKI的抗性。降低的EGFR-AS1水平使剪接向EGFR亚型D转移，从而导致配体介导的途径活化。在涉及患者和患者衍生异种移植（PDX）模型的临床试验中，在EGFR-Q787Q的A / A基因型，EGFR-AS1的低表达和EGFR同工型D的高表达的背景下，肿瘤缩小最为明显。我们的研究揭示了“沉默”突变如何影响lncRNA的水平，从而导致非典型的EGFR成瘾，并描绘了一种新的预测性生物标志物套件，用于响应EGFR TKIs。