Tang Z, Jiang S, Du R, Petri E T, El-Telbany A, Chan P S O, Kijima T, Dietrich S, Matsui K, Kobayashi M, Sasada S, Okamoto N, Suzuki H, Kawahara K, Iwasaki T, Nakagawa K, Kawase I, Christensen J G, Hirashima T, Halmos B, Salgia R, Boggon T J, Kern J A, Ma P C
Division of Hematology/Oncology, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center and Ireland Cancer Center, Case Comprehensive Cancer Center, Cleveland, OH 44106, USA.
Oncogene. 2009 Jan 29;28(4):518-33. doi: 10.1038/onc.2008.411. Epub 2008 Nov 17.
Targeted therapy against epidermal growth factor receptor (EGFR) represents a major therapeutic advance in lung cancer treatment. Somatic mutations of the EGFR gene, most commonly L858R (exon 21) and short in-frame exon 19 deletions, have been found to confer enhanced sensitivity toward the inhibitors gefitinib and erlotinib. We have recently identified an EGFR mutation E884K, in combination with L858R, in a patient with advanced lung cancer who progressed on erlotinib maintenance therapy, and subsequently had leptomeningeal metastases that responded to gefitinib. The somatic E884K substitution appears to be relatively infrequent and resulted in a mutant lysine residue that disrupts an ion pair with residue R958 in the EGFR kinase domain C-lobe, an interaction that is highly conserved within the human kinome as demonstrated by our sequence analysis and structure analysis. Our studies here, using COS-7 transfection model system, show that E884K works in concert with L858R in-cis, in a dominant manner, to change downstream signaling, differentially induce Mitogen-activated protein kinase (extracellular signaling-regulated kinase 1/2) signaling and associated cell proliferation and differentially alter sensitivity of EGFR phosphorylation inhibition by ERBB family inhibitors in an inhibitor-specific manner. Mutations of the conserved ion pair E884-R958 may result in conformational changes that alter kinase substrate recognition. The analogous E1271K-MET mutation conferred differential sensitivity toward preclinical MET inhibitors SU11274 (unchanged) and PHA665752 (more sensitive). Systematic bioinformatics analysis of the mutation catalog in the human kinome revealed the presence of cancer-associated mutations involving the conserved E884 homologous residue, and adjacent residues at the ion pair, in known proto-oncogenes (KIT, RET, MET and FAK) and tumor-suppressor gene (LKB1). Targeted therapy using small-molecule inhibitors should take into account potential cooperative effects of multiple kinase mutations, and their specific effects on downstream signaling and inhibitor sensitivity. Improved efficacy of targeted kinase inhibitors may be achieved by targeting the dominant activating mutations present.
针对表皮生长因子受体（EGFR）的靶向治疗是肺癌治疗领域的一项重大进展。已发现EGFR基因的体细胞突变，最常见的是L858R（第21外显子）和框内第19外显子短缺失，会使肿瘤细胞对吉非替尼和厄洛替尼抑制剂的敏感性增强。我们最近在一名晚期肺癌患者中发现了一种EGFR突变E884K，该患者在厄洛替尼维持治疗期间病情进展，随后出现软脑膜转移，对吉非替尼有反应。体细胞E884K替代似乎相对少见，它导致了一个突变的赖氨酸残基，该残基破坏了与EGFR激酶结构域C叶中R958残基的离子对，正如我们的序列分析和结构分析所示，这种相互作用在人类激酶组中高度保守。我们在此使用COS-7转染模型系统进行的研究表明，E884K以显性方式与顺式L858R协同作用，改变下游信号传导，差异诱导丝裂原活化蛋白激酶（细胞外信号调节激酶1/2）信号传导及相关细胞增殖，并以抑制剂特异性方式差异改变ERBB家族抑制剂对EGFR磷酸化的抑制敏感性。保守离子对E884-R958的突变可能导致构象变化，从而改变激酶底物识别。类似的E1271K-MET突变赋予了对临床前MET抑制剂SU11274（无变化）和PHA665752（更敏感）的不同敏感性。对人类激酶组突变目录的系统生物信息学分析揭示，在已知的原癌基因（KIT、RET、MET和FAK）和肿瘤抑制基因（LKB1）中存在涉及保守的E884同源残基以及离子对相邻残基的癌症相关突变。使用小分子抑制剂的靶向治疗应考虑多种激酶突变的潜在协同作用，以及它们对下游信号传导和抑制剂敏感性的特定影响。通过靶向存在的显性激活突变，可能提高靶向激酶抑制剂的疗效。
