Therapeutic strategies against EGFR exon 20 mutant lung cancer

EGFR外显子20突变肺癌的治疗策略

• 批准号: 10062900
• 负责人: John V. Heymach
• 金额: $ 55.75万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062900
• 关键词: Address; Bypass; Cancer Patient; Cell Line; Clinical; Clinical Research; Clinical Trials; Collaborations; DNA Sequence Alteration; Data; Development; Drug resistance; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Evaluable Disease; Exons; FDA approved; Future; Gefitinib; Generations; Genetically Engineered Mouse; Genomics; Goals; In Vitro; Induced Mutation; Insertion Mutation; Lead; Letters; Location; Malignant neoplasm of lung; Maps; Mediating; Medical Oncology; Medicine; Modeling; Molecular; Mutation; Nature; Non-Small-Cell Lung Carcinoma; Outcome; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Point Mutation; Population; Pre-Clinical Model; Productivity; Proteomics; Publications; Regimen; Reporting; Research Personnel; Resistance; Resistance development; Resources; Role; Signal Pathway; Signal Transduction; Structure; Structure-Activity Relationship; Study models; Testing; Therapeutic; Treatment Protocols; Tyrosine Kinase Inhibitor; aurora kinase A; base; combat; drug sensitivity; effective therapy; experience; improved; in silico; in vivo; inhibitor/antagonist; molecular modeling; molecular pathology; mouse model; multidisciplinary; mutant; objective response rate; partial response; patient population; phase II trial; pre-clinical; preclinical study; prevent; resistance mechanism; resistance mutation; response; screening; targeted agent; targeted treatment; treatment strategy; tumor; virtual

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.

项目摘要 EGFR突变的非小细胞细胞肺癌（NSCLC）患者约有10-12％的框架内 EGFR的外显子20中的突变或插入与NSCLC患者不同 （L858R或外显子19缺失），这些外显子20突变患者对FDA批准的第一次突变具有高度抗性 产生的酪氨酸激酶抑制剂（TKI），例如厄洛替尼或吉非替尼，客观响应率为 相比之下，大约4-8％的PFS为2个月； 典型的EGFR突变患者的反应率〜60％和〜10个月 受EGFR外显子20突变的影响是大小：美国约有2,000-3,000名患者， 在全球范围内，珀斯大约有27,000年。 是针对这个人群量身定制的。 分析和筛选工作导致将TKI poziotinib鉴定为有效的临床活动 EGFR外显子20突变肿瘤的抑制剂。 poziotinib。 在44名可评估患者中，有55％的患者对治疗没有反应（初级抗药性） 而且，对于最初反应的患者，获得的抵抗是我们的临床挑战。 阐明对poziotinib和其他潜在EGFR外显子20-的抗性和获得性的机制20- 有针对性的疗法。 特定插入的位置，与较低的α-c螺旋插入更大距离 对poziotinib的敏感性。 表明通过多种机制介导获得的分辨率MAY，某些EGFR依赖性（例如， 其他EGFR改变）和其他无关EGFR（例如激活替代信号的激活 途径）。 可以根据插入大小，位置和处理来决定根据最多的B量身定制 获得的抵抗是通过EGFR依赖性和独立机制发生的 有针对性的。 研究，分子建模和持续的临床研究。 特定插入和药物反应之间的结构 - 功能关系；我们将调查 EGFR依赖性获得的抗性的机制，在AIM 3中，我们将研究EGFR-INDENDENDENDENDENT 这些研究将有助于指导TKIS的选择 未来开发TKI和更有效组合的路线图，以延迟或防止 这组不存在靶向治疗的患者中耐药性的出现。