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Temporal resolution of autophosphorylation for normal and oncogenic forms of EGFR and differential effects of gefitinib

机译：正常和致癌形式的EGFR自身磷酸化的时间分辨以及吉非替尼的差异作用

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Epidermal growth factor receptor (EGFR) is a member of the ErbB family of receptor tyrosine kinases (RTK). EGFR overexpression or mutation in many different forms of cancers has highlighted its role as an important therapeutic target. Gefitinib, the first small molecule inhibitor of EGFR kinase function to be approved for the treatment of nonsmall cell lung cancer (NSCLC) by the FDA, demonstrates clinical activity primarily in patients with tumors that harbor somatic kinase domain mutations in EGFR. Here, we compare wild-type EGFR autophosphorylation kinetics to the L834R (also called L858R) EGFR form, one of the most common mutations in lung cancer patients. Using rapid chemical quench, time-resolved electrospray mass spectrometry (ESI-MS), and Western blot analyses, we examined the order of autophosphorylation in wild-type (WT) and L834R EGFR and the effect of gefitinib (Iressa) on the phosphorylation of individual tyrosines. These studies establish that there is a temporal order of autophosphorylation of key tyrosines involved in downstream signaling for WT EGFR and a loss of order for the oncogenic L834R mutant. These studies also reveal unique signature patterns of drug sensitivity for inhibition of tyrosine autophosphorylation by gefitinib: distinct for WT and oncogenic L834R mutant forms of EGFR. Fluorescence studies show that for WT EGFR the binding affinity for gefitinib is weaker for the phosphorylated protein while for the oncogenic mutant, L834R EGFR, the binding affinity of gefitinib is substantially enhanced and likely contributes to the efficacy observed clinically. This mechanistic information is important in understanding the molecular details underpinning clinical observations as well as to aid in the design of more potent and selective EGFR inhibitors.
机译：表皮生长因子受体（EGFR）是受体酪氨酸激酶（RTK）的ErbB家族的成员。在许多不同形式的癌症中，EGFR的过度表达或突变突出了其作为重要治疗靶点的作用。吉非替尼是首个被FDA批准用于治疗非小细胞肺癌（NSCLC）的EGFR激酶功能小分子抑制剂，主要在具有EGFR体细胞激酶结构域突变的肿瘤患者中证明了其临床活性。在这里，我们将野生型EGFR自磷酸化动力学与L834R（也称为L858R）EGFR形式进行比较，后者是肺癌患者中最常见的突变之一。使用快速化学淬灭，时间分辨电喷雾质谱（ESI-MS）和Western印迹分析，我们研究了野生型（WT）和L834R EGFR中自磷酸化的顺序以及吉非替尼（Iressa）对磷酸化的影响。个别酪氨酸。这些研究表明，WT EGFR下游信号传导中涉及的关键酪氨酸的自磷酸化存在时间顺序，而致癌L834R突变体则失去顺序。这些研究还揭示了吉非替尼抑制酪氨酸自磷酸化的药物敏感性的独特特征性模式：对于WT和致癌L834R突变形式的EGFR而言是不同的。荧光研究表明，对于WT EGFR，吉非替尼对磷酸化蛋白的结合亲和力较弱，而对于致癌突变体L834R EGFR，吉非替尼的结合亲和力则大大提高，可能有助于临床观察到的疗效。该机理信息对于理解支持临床观察的分子细节以及有助于设计更有效和选择性的EGFR抑制剂非常重要。

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