Unmet needs for specific subsets of EGFR mutated lung cancer

摘要/项目总结 肺癌是美国男性和女性癌症相关死亡率的主要原因。的 肺癌的新病例数每年超过220，000例;五年生存率为16%， 非小细胞肺癌（NSCLC）。拟议研究的总体目标是减少痛苦， 改善携带表皮生长因子受体（EGFR，ErbB 1）或ERBB 2突变的NSCLC的存活率 (i.e., >所有NSCLC的20%;全世界癌症死亡的最常见原因）。EGFR突变的NSCLC 包括具有独特生物学特征的疾病，其主要由涉及框内的靶向突变标记， 外显子19的插入缺失和点突变L 858 R。一些酪氨酸激酶抑制剂（TKI）可有效抑制 从这些异常激酶的信号传导，破坏其下游信号级联并诱导凋亡。 TKI目前已临床上市（吉非替尼、厄洛替尼、阿法替尼和奥希替尼）或正在开发中作为缓解药物 晚期EGFR突变NSCLC的治疗。然而，第三组最常见的EGFR突变， NSCLC（>10%的病例）由框内插入（跨越残基E762至E764的1-4个氨基酸）组成。 C775），对获批EGFR TKI不敏感。因此， 对于EGFR 20号外显子插入突变的NSCLC，能够或不能消除激酶活性的治疗对于 了解精确疗法对这组肿瘤的承诺和局限性。近同调 EGFR和ErbB 2插入突变的发生率表明，EGFR 20号外显子插入的未来治疗选择 突变将适用于其他NSCLC队列。该提案将利用我们的萌芽 全面的模型，以完全表征EGFR 20号外显子突变体，并确定新的治疗方法， 肿瘤的基因组亚组。目标1将建立稳健的临床前模型来代表EGFR 20号外显子 插入突变作为一个同质组;与产生新的模型，是必要的， 评估针对这些NSCLC的疗法。目标2将评价针对EGFR的可用和新型疗法 外显子20突变体;目的是确定有效的治疗方法-包括EGFR/ERBB 2外显子20突变体 特异性TKI及其假定的耐药机制。目标3将支持一种 EGFR/ERBB 2 20号外显子突变体特异性TKI;目的是证实此类药物的临床疗效。 药物和设计合理的联合疗法，以防止获得性耐药性的发展。的 这些模型的最终转化目标是提供合理的概念， 验证性临床试验和随后的患者临床护理。如果这些目标得以实现， 患者的生存期将超过目前的水平。

ABSTRACT/PROJECT SUMMARY Lung cancer is the leading cause of cancer-related mortality for both men and women in the United States. The number of new cases of lung cancer exceeds 220,000 yearly; with an appalling five year survival of 16% for non-small-cell lung cancer (NSCLC). The overall goal of the proposed research is to decrease suffering and improve survival for NSCLCs harboring epidermal growth factor receptor (EGFR, ErbB1) or ERBB2 mutations (i.e., >20% of all NSCLCs; the most common cause of cancer death worldwide). EGFR mutated NSCLCs comprise diseases with a distinct biology marked predominantly by targetable mutations involving inframe indels in exon 19 and the point mutation L858R. Some tyrosine kinase inhibitors (TKIs) can effectively inhibit signaling from these aberrant kinases, disrupt their downstream signaling cascades and induce apoptosis. TKIs are now clinically available (gefitinib, erlotinib, afatinib and osimertinib) or in development as palliative therapies for advanced EGFR mutated NSCLC. However, the third most prevalent group of EGFR mutations in NSCLC (>10% of cases) is composed of inframe insertions (of 1-4 amino-acids spanning residues E762 to C775) within exon 20 of EGFR that are insensitive to approved EGFR TKIs. Therefore, the identification of therapies that can or not abrogate kinase activity for EGFR exon 20 insertion mutated NSCLCs are essential to understand the promises plus limitations of precisions therapies for this cohort of tumors. The close homology of EGFR and ErbB2 insertion mutations highlights that future therapeutic options for EGFR exon 20 insertion mutations will be applicable to other cohorts of NSCLC. The proposal will take advantage of our budding comprehensive models to completely characterize EGFR exon 20 mutants and identify novel therapies for this genomic subgroup of tumors. Aim 1 will establish robust preclinical models to represent EGFR exon 20 insertion mutations as a homogenous group; with a goal of generating novel models that are necessary to evaluate therapies against these NSCLCs. Aim 2 will evaluate available and novel therapies against EGFR exon 20 mutants; with a goal of identifying effective therapies - including EGFR/ERBB2 exon 20 mutant specific TKIs – and their putative mechanisms of resistance. Aim 3 will support the clinical development of an EGFR/ERBB2 exon 20 mutant specific TKI; with a goal of confirming the clinical efficacy of such a class of drugs and designing rational combination therapies to prevent the development of acquired resistance. The final translational goals of these models are to provide rational concepts that can be explored initially in confirmatory clinical trials and subsequently in the clinical care of patients. If these goals are met, quality of life and survival of patients will be extended beyond what is currently available.