Molecular Mechanisms of EGF Signaling & Iressa/Tarceva Inhibition in NSCLC

描述(申请人提供)：表皮生长因子受体(EGFR)酪氨酸激酶通路已被证明是癌症治疗的关键分子靶点，包括TKI，如易瑞沙(Gefinitib)和Tarceva(Erlotinib)。这些化合物是小分子ATP模拟物，选择性地与EGFR的细胞内激酶结合，最近获得FDA批准用于治疗非小细胞肺癌(NSCLC)。越来越多的数据表明，EGFR突变的存在在TKI治疗和耐药性的反应中发挥着重要作用。有一组患者(约10%)对易瑞沙和Tarceva有显着反应，现在已与肿瘤内出现的几个特定的激活EGFR突变有关。在最初对药物敏感的复发患者中发现了第二种突变，最近在一个有患肺癌遗传倾向的家庭中也发现了这种突变。我们实验室和其他实验室最近的研究表明，下游信号的调制正在出现一种新的范式。这些研究表明，RTK的自动磷酸化以特定的顺序发生，创建了不同中间组磷酸酪氨酸的临时和动态磷酸化模式。因此，这些离散的磷酸酪氨酸可以以一种暂时的方式协调特定下游信号伙伴的动态招募，这可能在蛋白质信号的适当调节中发挥重要作用。EGFR的致癌激活和耐药突变以及对易瑞沙和Tarceva的差异敏感性的潜在分子机制尚不清楚。我们的初步数据表明，潜在的原因可能与受体的核苷酸亲和力、激酶催化活性的变化和/或导致蛋白质信号差异的磷酸化模式的变化有关。本申请中概述的研究将结合体外生化研究和互补细胞研究来确定特定的分子变化，这些变化可能区分野生型(WT)和致癌形式的EGFR，这些EGFR含有易瑞沙/Tarceva敏感的激活突变以及与耐药性相关的突变。总体目标是明确在正常和异常致癌过程中EGFR通路中蛋白质信号的分子机制，并为了解Iressa/Tarceva的调控作用提供依据。这些信息最终将有助于设计更有效和更具选择性的化合物，用于精确靶向的癌症治疗。 生长因子与位于细胞表面的相应受体结合，为细胞生长提供信号。在癌细胞中，细胞生长的信号具有异常的信号，生长和增殖变得失控。最新、最有希望的癌症疗法，如易瑞沙和Tarceva，针对的是癌细胞中这些不受控制的信号通路。一些非小细胞肺癌患者的生长因子受体有特殊突变，对这些药物有很好的反应，但其分子事件尚不清楚。本申请中描述的研究旨在帮助解开这些分子细节，使我们能够区分癌细胞和正常细胞，并评估当前和新的癌症治疗方法的有效性。

DESCRIPTION (provided by applicant): The epidermal growth factor receptor (EGFR) tyrosine kinase pathway has been demonstrated to be a key molecular target for cancer therapeutics including TKIs such as Iressa (gefinitib) and Tarceva (erlotinib). These compounds are small molecule ATP mimetics, selectively binding to the intracellular kinase of EGFR, that have recently received FDA approval for treatment of non-small cell lung carcinoma (NSCLC). An ever growing body of data indicates that the presence of mutations in EGFR play an important role in response to TKI therapy and drug resistance. There are a subset of patients (~10%) who have a remarkable response to Iressa and Tarceva that have now been correlated to several specific activating EGFR mutations arising within the tumor. A second mutation has been identified in relapsed patients who were initially drug responsive and more recently this mutation has also been found in a family with a genetic predisposition for developing lung cancer. Recent studies from our lab and others suggest an emerging new paradigm for modulation of downstream signaling. These studies show that autophosphorylation of RTKs occurs in a specific sequential order, creating a temporal and dynamic phosphorylation pattern of different intermediate sets of phosphotyrosines. Accordingly, these discrete sets of phosphotyrosines can orchestrate the dynamic recruitment of specific downstream signaling partners in a temporal fashion that may well play an important role in the proper regulation of protein signaling. The underlying molecular mechanisms of the oncogenic activating and resistance mutations in EGFR and differential sensitivity to Iressa and Tarceva are not understood. Our preliminary data suggest that the underlying causes may be linked to alterations in nucleotide affinity for the receptor, kinase catalytic activity, and/or alterations in phosphorylation patterns that result in differential protein signaling. The studies outlined in this application will use a combination of in vitro biochemical studies and complementary cellular studies to identify specific molecular alterations that may distinguish wild type (WT) and oncogenic forms of EGFR harboring Iressa/Tarceva sensitive activating mutations as well as mutations associated with drug resistance. The overall objectives are to define the molecular mechanism of protein signaling in the EGFR pathway under normal and aberrant oncogenic processes and provide an understanding for the modulating effects of Iressa/Tarceva. This information will ultimately aid in the design of more potent and selective compounds for precisely targeted cancer therapy. Growth factors bind to their corresponding receptors located on the surface of cells and give signals for cell growth. In a cancer cell, the signals for cell growth have aberrant signaling and growth and proliferation have become out of control. The newest, most promising cancer therapies such as Iressa and Tarceva, targets these uncontrolled signaling pathways in cancer cells. Some patients with non- small cell lung carcinoma having particular mutations in their growth factor receptors respond very well to these drugs, however the molecular events are not understood. The studies described in this application are designed help unravel these molecular details to allow us to differentiate cancer cells from normal cells and assess the usefulness of current and new cancer therapies.