Project 1: Development of pharmacologic strategies to degrade mutant EGFR.

检测表皮生长因子受体（EGFR）酪氨酸激酶结构域的体细胞突变 在10-15%的白人和30-40%的亚洲非小细胞肺癌（NSCLC）患者中。EGFR 酪氨酸激酶抑制剂（TKI），包括吉非替尼、厄洛替尼和阿法替尼，是最初的标准治疗。 晚期EGFR突变型肺癌患者的治疗。尽管绝大多数患者 EGFR抑制剂治疗显著减少肿瘤，获得性耐药性不可避免地在肿瘤中发展。 大多数患者。对于获得性耐药的最常见机制，EGFR T790 M，在60%的患者中检测到。 奥希替尼（AZD 9291），一种化学多样的（嘧啶;吉非替尼，厄洛替尼和阿法替尼）， 喹唑啉）突变选择性共价EGFR抑制剂，在>60%的患者中临床有效， 最近在美国、欧洲和日本被批准用于临床。 然而，突变选择性EGFR抑制剂的耐药机制已经开始被确定， 在临床前模型和患者中。这些包括EGFR C797 S，奥希替尼的共价结合位点， 我们通过对奥希替尼治疗后复发的患者的血浆DNA进行测序来鉴定。 值得注意的是，导致奥希替尼耐药的EGFR突变保留了对喹唑啉类药物的敏感性。 EGFR抑制剂，包括吉非替尼（当存在时，不存在EGFR T790 M）。与此相反， 三种EGFR突变（EGFR激活突变，EGFR T790 M和EGFR C797 S）对所有目前的 EGFR抑制剂。与Michael Eck（核心B;结构）合作，我们最近发现并研究了 一种新的突变体选择性变构EGFR抑制剂（EAI 045）。与西妥昔单抗联合使用，EAI 045有效 在携带C797 S的EGFR突变体模型中的体外和体内研究表明， 这些方法可以鉴定出即使在多种药物存在下也能抑制突变EGFR的独特策略 EGFR TKI耐药突变。 目前的临床范式是用连续的单药EGFR治疗EGFR突变型肺癌患者 TKI。然而，我们最近的临床前研究表明，奥希替尼和吉非替尼可以克服非 重叠EGFR介导的耐药突变，表明两种药物的双重EGFR抑制作用 这可能是一个更有效的策略。在目前的提案中，我们将评估和制定新的战略， 特别是突变的选择性EGFR特异性降解剂，确定这些方法是否单独或与 与现有的ATP竞争性EGFR抑制剂组合，克服和/或更有效地限制 耐药性的出现比连续的单一药物治疗。

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) are detected in 10-15% of Caucasian and 30-40% of Asian patients with non-small cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs), including gefitinib, erlotinib and afatinib, are the standard of care initial treatment for patients with advanced EGFR mutant lung cancer. Although the vast majority of patients have significant tumor reductions with EGFR inhibitor treatment, acquired drug resistance inevitably develops in the majority of patients. For the most common mechanism of acquired resistance, EGFR T790M, detected in 60% of patients, osimertinib (AZD9291), a chemically diverse (pyrimidine; gefitinib, erlotinib and afatinib are quinazolines) mutant selective covalent EGFR inhibitor, is clinically effective in >60% of patients and has recently been approved for clinical use in the United States, Europe and Japan. However, resistance mechanisms to mutant selective EGFR inhibitors have already begun to be identified both in preclinical models and from patients. These include EGFR C797S, the site of covalent binding of osimertinib, which we identified by sequencing of plasma DNA from patients who relapsed on osimertinib treatment. Remarkably, EGFR mutations that cause resistance to osimertinib retain sensitivity to quinazoline based EGFR inhibitors including gefitinib when present in the absence of EGFR T790M. In contrast cancers with three EGFR mutations (EGFR activating mutation, EGFR T790M and EGFR C797S) are resistant to all current EGFR inhibitors. In collaboration with Michael Eck (Core B; structure), we have recently identified and studied a novel mutant selective allosteric EGFR inhibitor (EAI045). In conjunction with cetuximab EAI045 is effective both in vitro and in vivo in EGFR mutant models harboring C797S suggesting that novel drug development approaches can identify unique strategies to inhibiting mutant EGFR even in the presence of multiple drug resistance mutations to EGFR TKIs. The current clinical paradigm is to treat EGFR mutant lung cancer patients with successive single agent EGFR TKIs. Our recent preclinical studies, however, demonstrate that osimeritinib and gefitinib can overcome non- overlapping EGFR mediated drug resistance mutations, suggesting that dual EGFR inhibition with both agents may be a more effective strategy. In the current proposal we will evaluate and develop new strategies, specifically mutant selective EGFR specific degraders, determine whether such approaches, alone or in combination with existing ATP competitive EGFR inhibitors, overcome and/or more effectively limit the emergence of drug resistance than successive single agent treatments.