Circumventing Acquired Resistance to Growth Factor Receptor Kinase Inhibitors

摘要 酪氨酸激酶抑制剂在肿瘤分子靶向治疗中的应用 传统知识机构面临着许多困难的挑战。其中最重要的是， 确定对靶向药物唯一敏感的不同癌症的子集，通常 通过遗传标记的存在来识别，这些遗传标记暗示着对药物的依赖性或成瘾性。 目标路径。对于这些疗法的长期成功同样重要的是 了解和规避获得性耐药性，这是一个关键的限制， 其临床效果。获得性生长因子受体耐药 与对遗传毒性癌症化疗的耐药性不同，可能包括两种特异性 靶向受体的突变，以及更复杂的功能改变， 信令网络在这里，我们将使用非小细胞肺癌（NSCLC）细胞系 这些模型似乎忠实地概括了癌症的关键信号依赖性， 表皮生长因子受体（EGFR）基因的激活突变， 对EGFR TKI极度敏感的肺癌亚组。我们概述了三个目标 解决以前对药物敏感的肿瘤获得耐药性的问题 在目标1中，我们将产生获得性耐药的细胞系模型， EGFR的<$第二代<$不可逆抑制剂，并使用遗传，信号和 功能分析，剖析潜在的机制。在目标2中，我们将使用高 通过酪氨酸激酶的shRNA筛选来鉴定候选靶标， 抑制可以避免对EGFR抑制剂的耐药性。在目标3中，我们将使用 慢病毒敲减/重建实验以定量 耐药细胞，包括起始EGFR突变和相关信号传导 导致获得性耐药性的途径。这些目标将共同提供 重要的洞察力的关键机制，获得耐药性， 靶向人类癌症中生长因子受体的新型抑制剂。公共卫生相关性 了解对新类别敏感的癌症的机制 靶向癌症治疗的耐药性对他们最终的临床治疗至关重要。 成功我们的方法旨在剖析耐药的分子基础， 抗癌药

ABSTRACT The success of molecularly targeted cancer therapy using tyrosine kinase inhibitors (TKIs) faces a number of difficult challenges. Foremost among these is the ability to identify subsets of different cancers that are uniquely sensitive to targeted agents, often identified by the presence of genetic markers implying ¿dependence¿ or `addiction¿ to the targeted pathway. Equally important to the longterm success of these therapies is understanding and circumventing acquired drug resistance, which is a key limitation to their clinical effectiveness. Acquired resistance to drugs targeting growth factor receptors differs from resistance to genotoxic cancer chemotherapy, and may include both specific mutations in targeted receptors, as well as more complex functional alterations in signaling networks. Here we will use non-small cell lung cancer (NSCLC) cell line models that appear to faithfully recapitulate key signaling dependence of cancers with activating mutations in the Epidermal Growth Factor Receptor (EGFR) gene, identifying a subset of lung cancers with extreme sensitivity to EGFR TKIs. We outline three aims that address the acquisition of resistance in tumors that were previously sensitive to these agents: in Aim 1, we will generate cell line models for acquired resistance to ¿second generation¿ irreversible inhibitors of EGFR, and use genetic, signaling and functional analyses to dissect the underlying mechanisms. In Aim 2, we will use a high throughput shRNA screen of tyrosine kinases to identify candidate targets whose suppression may circumvent resistance to EGFR inhibitors. In Aim 3, we will use lentiviral knockdown/reconstitution experiments to quantitate oncogene dependence of drug resistant cells, both on the initiating EGFR mutation and on associated signaling pathways that contribute to acquired drug resistance. Together, these aims will provide important insight into critical mechanisms that underlie the acquisition of resistance to novel inhibitors targeting growth factor receptors in human cancer. Public Health relevance Understanding the mechanisms by which cancers that are sensitive to the new classes of targeted cancer therapies become resistant to these is critical to their eventual clinical success. Our approach is designed to dissect the molecular basis of resistance to these cancer drugs.