Therapeutic strategies against EGFR exon 20 mutant lung cancer

项目摘要 约10-12%的EGFR突变非小细胞肺癌（NSCLC）患者携带符合读框的 EGFR外显子20内的突变或插入。与携带“典型”EGFR突变的NSCLC患者不同 （L 858 R或外显子19缺失），这些具有外显子20突变的患者对FDA批准的第一种药物高度耐药。 第二代酪氨酸激酶抑制剂（TKI），如厄洛替尼或吉非替尼，客观缓解率为 约4-8%，中位PFS为2个月;相比之下，第一代TKI的目标是 典型EGFR突变患者的缓解率约为60%，PFS约为10个月。人口 受EGFR 20号外显子突变影响的患者数量相当大：美国每年约有2000 - 3000例患者， 全球每年约有27，000名患者。直到最近，还没有确定治疗策略 是为这个病人群体量身定做的。我们最近报道了一个详细的结构-功能的结果 分析和筛选工作，导致TKI poziotinib被鉴定为一种有效的临床活性药物， EGFR 20号外显子突变型肿瘤抑制剂。根据我们的临床前数据，我们进行了一项II期试验， poziotinib。初步结果表明，高抗肿瘤活性，最佳客观缓解为PR（部分缓解）， 44例可评价患者中的55%。然而，有些患者最初对治疗没有反应（原发性耐药） 而对于最初确实有反应的患者来说，获得性耐药性是一个临床挑战。我们的目标是 阐明对Poziotinib和其他潜在EGFR 20号外显子的原发性和获得性耐药机制- 靶向治疗。我们发现，在临床前模型中，原发性耐药可能与大小有关， 特定插入的位置，与α-c-螺旋的插入距离越大， 对Poziotinib敏感。此外，我们已经从临床前模型和NSCLC患者中获得了证据， 表明获得性抗性可能通过多种机制介导，一些EGFR依赖性（例如， 其他EGFR改变）和其他EGFR非依赖性（例如激活替代信号旁路 路径）。我们假设a）不同的20号外显子插入/突变对特定TKI的敏感性将 由插入尺寸和位置决定，并且可以基于该信息来定制治疗;以及B） 获得性耐药性通过EGFR依赖性和独立机制发生， 针对性地我们将通过涉及临床前研究的综合性、多学科的努力来测试这些假设。 研究、分子建模和正在进行的临床研究。在目标1中，我们将研究原发性耐药性， 特异性插入和药物反应之间的结构-功能关系;在目标2中，我们将研究 EGFR依赖性获得性耐药的机制，在目标3中，我们将研究EGFR非依赖性 机制等这些研究将有助于指导基于患者突变的TKI选择，并将提供 为未来开发改进的TKI和更有效的组合以延迟或预防 在这组患者中出现耐药性，目前还没有针对性治疗。

PROJECT SUMMARY Approximately 10-12% of non-small cell lung cancer (NSCLC) patients with EGFR mutations harbor in-frame mutations or insertions within exon 20 of EGFR. Unlike NSCLC patients bearing “typical” EGFR mutations (L858R or exon 19 deletions), these patients with exon 20 mutations are highly resistant to FDA-approved first- generation tyrosine kinase inhibitors (TKIs) such as erlotinib or gefitinib, with an objective response rate of approximately 4-8% and a median PFS of 2 months; by comparison, first-generation TKIs lead to an objective response rate of ~60% and a PFS of ~10 months in patients with typical EGFR mutations. The population impacted by EGFR exon 20 mutations is sizable: approximately 2,000-3,000 patients per year in the US and approximately 27,000 patients per year worldwide. Until recently, no treatment strategies had been identified that were tailored for this patient population. We recently reported the results of a detailed structure-function analysis and screening effort that led to the identification of the TKI poziotinib as a potent and clinically active inhibitor of EGFR exon 20 mutant tumors. Based on our preclinical data we have conducted a phase II trial of poziotinib. Initial results indicate high anti-tumor activity with best objective response of PR (partial response) in 55% of 44 evaluable patients. However, some patients do not initially respond to treatment (primary resistance) and, for the patients who do respond initially, acquired resistance is a clinical challenge. Our goals are to elucidate the mechanisms of primary and acquired resistance to poziotinib and other potential EGFR exon 20- targeted therapies. We find that in preclinical models, primary resistance may be associated with size and location of the specific insertion, with a greater distance of the insertion from the α-c-helix associated with a lower sensitivity to poziotinib. Moreover, we have generated evidence from preclinical models and NSCLC patients indicating that acquired resistance may be mediated through multiple mechanisms, some EGFR-dependent (e.g. additional EGFR alterations) and others EGFR-independent (e.g. activation of alternate signal bypass pathways). We hypothesize that a) the sensitivity of different exon 20 insertions/mutations to specific TKIs will be dictated by the insertion size and location and treatment may be tailored based on this information; and b) that acquired resistance occurs through both EGFR-dependent and independent mechanisms that can be targeted. We will test these hypotheses through an integrative, multidisciplinary effort involving preclinical studies, molecular modeling, and ongoing clinical studies. In Aim 1, we will investigate primary resistance and the structure-function relationship between specific insertions and drug response; in Aim 2, we will investigate the mechanisms of EGFR-dependent acquired resistance, and in Aim 3 we will investigate EGFR-independent mechanisms. These studies will help guide the selection of TKIs based on a patients’ mutation, and will provide a road map for the future development of improved TKIs and more effective combinations to delay or prevent the emergence of drug resistance in this group of patients for which no targeted treatments currently exist.