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

描述（由申请人提供）：表皮生长因子受体（EGFR）酪氨酸激酶途径已被证明是包括易瑞沙（吉非替尼）和特罗凯（埃洛替尼）等TKIs在内的癌症治疗药物的关键分子靶点。这些化合物是小分子ATP模拟物，选择性结合EGFR细胞内激酶，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突变的存在在对TKI治疗和耐药性的反应中起着重要作用。有一部分患者（约10%）对易瑞沙和特罗凯有显著的反应，现在已经与肿瘤内产生的几种特异性激活EGFR突变相关。在最初对药物有反应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易感性的家庭中也发现了这种突变。我们实验室和其他人最近的研究提出了下游信号调制的新范式。这些研究表明，rtk的自磷酸化以特定的顺序发生，形成了不同中间磷酸酪氨酸组的时间和动态磷酸化模式。因此，这些离散的磷酸酪氨酸可以在一段时间内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特罗凯的不同敏感性的潜在分子机制尚不清楚。我们的初步数据表明，潜在的原因可能与核苷酸对受体的亲和力、激酶催化活性和/或磷酸化模式的改变有关，这些改变导致了不同的蛋白质信号传导。本申请中概述的研究将结合体外生化研究和补充细胞研究，以确定可能区分野生型（WT）和致癌形式的EGFR，其中包含易瑞沙/特罗凯敏感激活突变以及与耐药性相关的突变。总体目标是确定正常和异常致癌过程中EGFR通路中蛋白质信号的分子机制，并为易瑞沙/特罗凯的调节作用提供理解。这些信息最终将有助于设计出更有效、更有选择性的化合物，用于精确靶向癌症治疗。

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.