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Modulation of death receptor 4 in EGFR-targeted cancer therapy

EGFR 靶向癌症治疗中死亡受体 4 的调节

基本信息

批准号：
10206047
负责人：
Shi-Yong Sun
金额：
$ 43.91万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-09 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10206047
关键词：
Address Animal Model Apoptosis Apoptotic Area Asians Binding Biochemical Biological Biological Assay Biological Process CCL2 gene Cancer Biology Cancer Patient Cancer cell line Cell Line Cell Surface Receptors Cells Cessation of life Clinic Clinical Coculture Techniques Data Detection Development Disease Progression Down-Regulation Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib Event Exons FDA approved Gefitinib Generations Genes Genetic Transcription Immune Immunologic Surveillance Induction of Apoptosis Inflammatory Ligands MEKs Malignant Neoplasms Malignant neoplasm of lung Measurement Mediating Methods Molecular Mutation Necrosis Neoplasm Circulating Cells Non-Small-Cell Lung Carcinoma Outcome Patients Pharmaceutical Preparations Pharmacology Point Mutation Pre-Clinical Model Production Proteins Receptor Inhibition Resistance Resistance development Role Sampling Secondary to Signal Transduction Specimen System TNFRSF10A gene Testing Therapeutic Time Transcription Factor AP-1 Treatment Efficacy Tumor Immunity Tumor Necrosis Factor Receptor Validation cancer cell cytokine gene cloning in vivo knock-down knockout gene mutant novel patient derived xenograft model pre-clinical promoter receptor refractory cancer resistance mutation response small molecular inhibitor targeted cancer therapy targeted treatment tumor tumor growth tumor-immune system interactions

项目摘要

Targeting epidermal growth factor receptor (EGFR) activating mutations, 90% of which present as an exon 19 deletion (Del19) or exon 21 point mutation (L858R), with first generation EGFR tyrosine kinase inhibitors (EGFR-TKIs; e.g., erlotinib and gefitinib) and the T790M resistance mutation with third generation EGFR-TKIs (e.g., AZD9291; TAGRISSOTM or osimertinib) has provided significant clinical benefit in patients with non-small cell lung cancer (NSCLC) harboring these mutations. Unfortunately, resistance to these EGFR-TKIs occurs in the clinic, resulting in disease progression. Hence, understanding the underlying mechanisms and developing effective strategies to overcome EGFR-TKI resistance is highly desirable and urgently needed in the clinic. Death receptor 4 (DR4; also known as TRAIL-R1 or TNFRSF10A) is a cell surface receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). It is generally thought that its activation, upon binding to TRAIL, induces apoptosis; this function is recognized as a critical mechanism of immunosurveillance against cancer cells. However, whether DR4 exerts other as yet unknown biological functions is unclear. Our preliminary data demonstrated that EGFR inhibition with several EGFR inhibitors including AZD9291, CO1686, and erlotinib substantially decreased DR4 levels primarily in EGFR-TKI-sensitive EGFR-mutant NSCLC cell lines; this DR4 reduction is tightly associated with ERK suppression and induction of apoptosis in the tested cell lines. Unexpectedly, knockdown of DR4 augments TRAIL-induced apoptosis and also enhances AZD9291- induced apoptosis. This proposal thus will test the overall hypothesis that suppression of DR4 expression is an on-target consequence of EGFR inhibition and has critical impact on both early and long-term therapeutic efficacy of EGFR-targeted therapy. This hypothesis will be tested by accomplishing the following specific aims: (1) to demonstrate the mechanism(s) by which EGFR inhibitors suppress DR4 expression; (2) to understand the biological significance of DR4 suppression in EGFR-targeted cancer therapy; and (3) to elucidate the effect of DR4 downregulation on the efficacy of EGFR-targeted therapy using preclinical NSCLC patient-derived xenografts (PDXs) and samples from NSCLC patients treated with EGFR-TKIs. The objectives of this proposal are to demonstrate the molecular mechanism underlying DR4 reduction caused by EGFR inhibition, to understand the biological significance of DR4 suppression in EGFR-targeted cancer therapy, and to validate DR4 downregulation in clinical specimens from NSCLC patients receiving EGFR-TKIs. We believe that the outcomes of this proposal will be of high translational significance with immediate impact on EGFR-targeted cancer therapy in the clinic. 1

靶向表皮生长因子受体 (EGFR) 激活突变，其中 90% 表现为外显子 19 缺失 (Del19) 或外显子 21 点突变 (L858R)，使用第一代 EGFR 酪氨酸激酶抑制剂（EGFR-TKI；例如厄洛替尼和吉非替尼）以及第三代 EGFR-TKI 的 T790M 耐药突变（例如 AZD9291；TAGRISSOTM 或奥西替尼）为非小细胞肺癌患者提供了显着的临床益处携带这些突变的细胞肺癌（NSCLC）。不幸的是，对这些 EGFR-TKI 的耐药性发生在诊所，导致疾病进展。因此，了解潜在机制并开发临床上非常需要和迫切需要克服 EGFR-TKI 耐药性的有效策略。死亡受体 4（DR4；也称为 TRAIL-R1 或 TNFRSF10A）是肿瘤坏死的细胞表面受体因子相关的凋亡诱导配体（TRAIL）。人们普遍认为，它的激活是在结合到 TRAIL，诱导细胞凋亡；该功能被认为是免疫监视的关键机制癌细胞。然而，DR4是否发挥其他未知的生物学功能尚不清楚。我们的初步数据表明，几种 EGFR 抑制剂（包括 AZD9291、CO1686、厄洛替尼显着降低了 EGFR-TKI 敏感的 EGFR 突变 NSCLC 细胞中的 DR4 水平线路；在测试中，DR4 的减少与 ERK 抑制和细胞凋亡诱导密切相关细胞系。出乎意料的是，DR4 的敲低增强了 TRAIL 诱导的细胞凋亡，也增强了 AZD9291- 诱导细胞凋亡。因此，该提案将检验以下总体假设：抑制 DR4 表达是一种 EGFR 抑制的靶向结果，对早期和长期治疗具有关键影响 EGFR靶向治疗的疗效。该假设将通过实现以下具体目标来检验： (1) 证明EGFR抑制剂抑制DR4表达的机制； (2)了解 DR4 抑制在 EGFR 靶向癌症治疗中的生物学意义； (3) 阐明效果 DR4 下调对使用临床前 NSCLC 患者来源的 EGFR 靶向治疗的疗效的影响异种移植物 (PDX) 和来自接受 EGFR-TKI 治疗的 NSCLC 患者的样本。本提案的目标旨在证明 EGFR 抑制引起 DR4 减少的分子机制，了解 DR4 抑制在 EGFR 靶向癌症治疗中的生物学意义，并验证接受 EGFR-TKI 治疗的 NSCLC 患者临床标本中 DR4 下调。我们相信该提案的结果将具有高度转化意义，对 EGFR 靶向产生直接影响临床癌症治疗。 1