Molecular features impacting drug resistance in atypical EGFR exon 18 and exon 20 mutant non-small cell lung cancers and the development of novel mutant-selective inhibitors

影响非典型 EGFR 外显子 18 和外显子 20 突变非小细胞肺癌耐药性的分子特征以及新型突变选择性抑制剂的开发

• 批准号: 10593969
• 负责人: John V. Heymach
• 金额: $ 56.65万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593969
• 关键词: Acceleration; Address; Adverse event; Affinity; Binding; Cancer Patient; Classification; Clinical; Clinical Data; Crystallography; Data; Development; Diarrhea; Dose; Drug Kinetics; Drug Screening; Drug resistance; ERBB2 gene; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Evaluable Disease; Exanthema; Exons; FDA approved; Generations; Genetically Engineered Mouse; In Vitro; Laboratory Scientists; Libraries; Malignant Neoplasms; Medicine; Modeling; Molecular; Mutation; Nature; Non-Small-Cell Lung Carcinoma; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Physicians; Population; Progression-Free Survivals; Receptor Inhibition; Reporting; Research Personnel; Resistance; Resources; Retrospective Studies; Specificity; Structural Biologist; Structure-Activity Relationship; Subgroup; Testing; Therapeutic Agents; Toxic effect; Translating; Tyrosine Kinase Inhibitor; Work; design; experience; improved; in silico; in vivo; inhibitor; insight; interdisciplinary approach; molecular dynamics; molecular modeling; multidisciplinary; mutant; novel; objective response rate; patient derived xenograft model; phase II trial; pre-clinical; prevent; rational design; receptor; research clinical testing; response; tumor

PROJECT SUMMARY Approximately 20% of non-small cell lung cancer (NSCLC) patients with EGFR mutations harbor atypical mutations. Unlike NSCLC patients bearing “classical” EGFR mutations (L858R or exon 19 deletions), the patients with atypical mutations in exon 18 or 20 are resistant to FDA-approved first-generation tyrosine kinase inhibitors (TKIs), with exon 20 patients presenting response rates of only 4-8% and a median progression free survival (mPFS) of 2 months based on retrospective studies. Similarly, patients with atypical EGFR exon 18 mutations have less clinical benefit than patients with classical EGFR mutations when treated with common EGFR- TKIs. The population impacted by atypical EGFR NSCLC mutations is sizable: approximately 5,000 patients per year in the US, 41,600 patients per year worldwide, and an even greater number of patients outside of NSCLC. We recently reported the results of a detailed structural and functional analysis that led to the identification of the TKI, poziotinib, as a potent and clinically active inhibitor of EGFR and HER2 exon 20 mutant tumors. Based on this data we have conducted an investigator-initiated phase II trial testing poziotinib in EGFR and HER2 exon 20 mutant NSCLC patients, demonstrating that it is highly active drug for with confirmed objective responses observed in 43% of patients. This clearly represents an advance for these patients, however, the drug has significant limitations. Responses to poziotinib treatment were of limited duration, with a mPFS of 5.5 months, and even less activity was observed in patients with mutations in the “far loop” of exon 20. Whereas patients with classical EGFR mutations have a mPFS of 18.9 months to osimertinib. Furthermore, many patients receiving poziotinib experienced >grade 3 adverse events, diarrhea and rash, related to the activity of this drug against wild-type EGFR, resulting in dose reduction in >60% of patients. To address these limitations, we propose an integrative analysis to understand the structural features of EGFR exon 18 and 20 mutations, so that more potent inhibitors can be developed and that specificity for mutant to WT receptor can be enhanced. To achieve this, we propose the following aims: Aim 1) we will study the structural features of EGFR exon 20 mutations that drive differential sensitivity to TKIs to guide the development of novel compounds with increased potency. Aim 2) we will analyze the structural features of atypical EGFR exon 18 mutations to use this information to rationally design new compounds with enhance efficacy. Aim 3) we will develop novel TKIs with improved EGFR mutant vs wild- type specificity to augment drug tolerability and clinical benefit of EGFR exon 18 and exon 20 mutant patients. We have assembled a unique, multi-disciplinary team of physicians, laboratory scientist, structural biologist, and medicinal chemists with unparalleled pre-clinical and clinical resources for who will work cooperatively to gain insights into the structural features of EGFR exon 18 and 20 mutant cancers and to translate this into preclinical and potentially clinical testing. Furthermore, insights gained from this study can help to accelerate efforts worldwide aiming to target EGFR exon 18 and 20 tumors as well as other EGFR mutant caners.

项目摘要 约20%的EGFR突变非小细胞肺癌（NSCLC）患者具有非典型性EGFR突变。 突变。与携带“经典”EGFR突变（L 858 R或外显子19缺失）的NSCLC患者不同， 外显子18或20中的非典型突变对FDA批准的第一代酪氨酸激酶抑制剂耐药 （TKI），外显子20患者的缓解率仅为4-8%，中位无进展生存期 （mPFS）2个月。同样，非典型EGFR外显子18突变患者 当使用普通EGFR TKI治疗时，其临床获益低于经典EGFR突变患者。 受非典型EGFR NSCLC突变影响的人群相当大：每年约5，000例患者 在美国，全球每年有41，600例患者，非NSCLC患者的数量甚至更多。我们 最近报道了详细的结构和功能分析的结果，这些分析导致了 TKI，poziotinib，作为EGFR和HER 2 20号外显子突变型肿瘤的强效和临床活性抑制剂。基于 根据这些数据，我们进行了一项研究药物启动的II期试验，检测poziotinib在EGFR和HER 2 20号外显子中的作用 突变型NSCLC患者，证明它是一种高活性药物，具有确认的客观缓解 在43%的患者中观察到。这显然代表了这些患者的进步，然而，这种药物 重大限制。对poziotinib治疗的反应持续时间有限，mPFS为5.5个月， 在外显子20的“远环”突变的患者中观察到的活性甚至更低。而患者 经典EGFR突变患者接受奥希替尼治疗的mPFS为18.9个月。此外，许多患者接受 poziotinib出现了> 3级不良事件，腹泻和皮疹，与该药物的抗肿瘤活性相关 野生型EGFR，导致>60%的患者剂量减少。为了解决这些限制，我们提出了一个 整合分析，了解EGFR外显子18和20突变的结构特征，以便更有效地 可以开发抑制剂，并可以增强突变体对WT受体特异性。因此我们 我们提出以下目标：目的1）我们将研究EGFR 20号外显子突变的结构特征，这些突变驱动EGFR 20号外显子突变。 对TKI的不同敏感性，以指导开发具有增加效力的新型化合物。目标2）我们 将分析非典型EGFR外显子18突变的结构特征，以利用这些信息合理设计 具有增强功效的新化合物。目的3）我们将开发具有改善的EGFR突变体与野生型相比的新型TKI。 型特异性，以增加EGFR外显子18和外显子20突变患者的药物耐受性和临床获益。 我们已经组建了一个独特的，多学科的医生，实验室科学家，结构生物学家， 拥有无与伦比的临床前和临床资源的药物化学家将与世卫组织合作， 深入了解EGFR外显子18和20突变型癌症的结构特征，并将其转化为临床前研究 和潜在的临床试验。此外，从这项研究中获得的见解有助于加快努力， 在全球范围内针对EGFR外显子18和20肿瘤以及其他EGFR突变型癌症。