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

• 批准号: 10653881
• 负责人: Shi-Yong Sun
• 金额: $ 42.27万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-09 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10653881
• 关键词: Address; Animal Model; Apoptosis; Apoptotic; Area; Asian; 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; Knock-out; Ligands; MEKs; Malignant Neoplasms; Malignant neoplasm of lung; Measurement; Mediating; Methods; Molecular; Mutation; Neoplasm Circulating Cells; Non-Small-Cell Lung Carcinoma; Outcome; Patients; Pharmaceutical Preparations; Point Mutation; Pre-Clinical Model; Production; Proteins; Receptor Inhibition; Resistance; Resistance development; Role; Sampling; Secondary to; Signal Transduction; Specimen; System; TNF gene; 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; mutant; novel; patient derived xenograft model; pharmacologic; pre-clinical; promoter; receptor; refractory cancer; resistance mutation; response; small molecular inhibitor; targeted cancer therapy; targeted treatment; tumor; tumor growth; tumor-immune system interactions

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％作为外显子19 删除（DEL19）或外显子21点突变（L858R），第一代EGFR酪氨酸激酶抑制剂 （egfr-tkis; （例如，AZD9291； Tagrissotm或Osimertinib）为非小型患者提供了显着的临床益处 具有这些突变的细胞肺癌（NSCLC）。不幸的是，对这些EGFR-TKI的抵抗发生在 诊所，导致疾病进展。因此，了解基本机制并发展 克服EGFR-TKI抗性的有效策略是高度可取的，并且在诊所中急需。 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 与因子相关的凋亡诱导配体（TRAIL）。通常认为它的激活在与 步道，诱导凋亡；该功能被认为是免疫监视的关键机制 癌细胞。但是，DR4是否施加其他尚不清楚的生物学功能尚不清楚。我们的 初步数据表明，EGFR抑制几种EGFR抑制剂，包括AZD9291，CO1686， Erlotinib主要降低了EGFR-TKI敏感的EGFR突变NSCLC细胞中的DR4水平 线；此DR4的减少与ERK抑制和诱导凋亡密切相关 细胞系。出乎意料的是，DR4的敲低增加了跟踪诱导的凋亡，并增强了AZD9291- 诱导凋亡。因此，该建议将检验总体假设，即DR4表达的抑制是 EGFR抑制的目标后果，对早期和长期治疗都有关键的影响 EGFR靶向疗法的功效。该假设将通过实现以下特定目的来检验： （1）证明EGFR抑制剂抑制DR4表达的机制； （2）理解 DR4抑制在EGFR靶向的癌症治疗中的生物学意义； （3）阐明效果 使用临床前NSCLC患者衍生的DR4下调对EGFR靶向疗法的功效 异种移植物（PDXS）和接受EGFR-TKIS治疗的NSCLC患者的样品。该提议的目标 要证明由EGFR抑制引起的DR4降低的分子机制， 了解DR4在EGFR靶向癌症治疗中抑制的生物学意义，并验证 NSCLC患者接受EGFR-TKIS的NSCLC患者的临床标本中的DR4下调。我们相信 该提案的结果将具有很高的翻译意义，并直接影响到EGFR。 诊所的癌症治疗。 1

项目成果

The novel MET inhibitor, HQP8361, possesses single agent activity and enhances therapeutic efficacy of AZD9291 (osimertinib) against AZD9291-resistant NSCLC cells with activated MET.

• 发表时间: 2020-10
• 期刊: American journal of cancer research
• 影响因子: 5.3
• 作者: Danlei Yu;Yiting Li;Keven Dy Sun;J. Gu;Zhen Chen;T. Owonikoko;S. Ramalingam;Shi-Yong Sun

Does the natural product, honokiol, have value in the battle against osimertinib resistance?

• DOI: 10.18632/oncoscience.517
• 发表时间: 2020-09
• 期刊: Oncoscience
• 作者: Vallega KA;Sun SY
• 通讯作者: Sun SY