Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Nat Struct Mol Biol. 2011 Nov 20;18(12):1388-93. doi: 10.1038/nsmb.2168.
Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is commonly activated by mutation in non-small cell lung cancer. The mechanism of this oncogenic activation is not completely understood, but in contrast to that of the wild-type EGFR, it is proposed to be independent of kinase domain dimerization. Mechanistic studies on EGFR have mainly relied on cell-based assays or isolated kinase domain measurements. Here we show, using purified, near full-length human EGFR proteins (tEGFRs), that two oncogenic mutants are fully active independently of EGF and highly resistant to the therapeutic and endogenous inhibitors cetuximab, lapatinib and MIG6. Based on the pattern of inhibition and the effects of additional asymmetric kinase dimer interface mutations, we propose that these oncogenic EGFR mutants drive and strongly depend on the formation of the asymmetric kinase dimer for activation, which has implications for drug design and cancer treatment strategies.
表皮生长因子受体 (EGFR) 是一种受体酪氨酸激酶，在非小细胞肺癌中通常通过突变激活。这种致癌激活的机制尚不完全清楚，但与野生型 EGFR 不同，它被认为独立于激酶结构域二聚化。EGFR 的机制研究主要依赖于基于细胞的测定或分离的激酶结构域测量。在这里，我们使用纯化的、近乎全长的人表皮生长因子受体蛋白 (tEGFR) 表明，两种致癌突变体在没有 EGF 的情况下完全具有活性，并且对治疗和内源性抑制剂西妥昔单抗、拉帕替尼和 MIG6 具有高度抗性。基于抑制模式和额外的不对称激酶二聚体界面突变的影响，我们提出这些致癌 EGFR 突变体驱动并强烈依赖于不对称激酶二聚体的形成来激活，这对药物设计和癌症治疗策略具有重要意义。
