Regulation of Death Receptor 5 folding and apoptotic signaling by AGR2

AGR2 对死亡受体 5 折叠和细胞凋亡信号的调节

• 批准号: 10042651
• 负责人: Brian K. Law
• 金额: $ 38.88万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-16 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10042651
• 关键词: Active Sites; Animals; Anterior; Antineoplastic Agents; Apoptosis; Apoptotic; Binding; Breast; Breast Epithelial Cells; CASP3 gene; CASP8 gene; Cell Death; Cell surface; Cells; Chemicals; Combined Modality Therapy; Cysteine; Development; Disulfides; Down-Regulation; Drug resistance; ERBB2 gene; ERBB3 gene; Endoplasmic Reticulum; Epidermal Growth Factor Receptor; Epithelial Cell Proliferation; Event; Exhibits; Extracellular Domain; Family; Genetic; In Vitro; Knock-out; Knowledge; Ligands; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Mammary Neoplasms; Mass Spectrum Analysis; Mediating; Modeling; Modification; Molecular; Molecular Chaperones; Monoclonal Antibodies; Normal tissue morphology; Oncoproteins; Outcome; Patients; Pharmacology; Play; Protein Disulfide Isomerase; Protein Tyrosine Kinase; Publishing; Refractory; Regimen; Regulation; Reporting; Resistance; Role; Signal Transduction; Site-Directed Mutagenesis; TNFRSF10A gene; TNFRSF10B gene; TNFSF10 gene; Testing; Therapeutic; Toxic effect; Up-Regulation; Weight; Xenopus laevis; aggressive therapy; angiogenesis; anti-cancer; antibody inhibitor; cancer cell; conventional therapy; cytokine; disulfide bond; enzyme activity; improved; in vivo; inhibitor/antagonist; kinase inhibitor; knock-down; lapatinib; malignant breast neoplasm; malignant stomach neoplasm; molecular targeted therapies; novel; novel strategies; overexpression; prevent; prostate cancer cell; receptor; receptor downregulation; response; senescence; small molecule inhibitor; targeted agent; targeted treatment; triple-negative invasive breast carcinoma; tumor; tumor xenograft

Description The Epidermal Growth Factor Receptor-family tyrosine kinases EGFR and HER2 are overexpressed in a significant proportion of aggressive, treatment-refractory breast cancers. This includes HER2+ tumors that have acquired resistance to HER2-specific monoclonal antibodies and kinase inhibitors and Triple-Negative Breast Cancers (TNBCs), of which approximately 50% overexpress EGFR. Agents that selectively kill EGFR+ or HER2+ tumors through a novel mechanism of action could improve the survival of patients with these treatment-refractory cancers. Our team reported a new class of anticancer compounds, termed DDAs, with selective toxicity against EGFR+ and HER2+ cancers. Published and preliminary results demonstrate that DDAs kill patient-derived breast xenograft tumors without detectable toxicity to experimental animals. DDAs kill cancer cells by activating Death Receptors 4 and 5 (DR4/5), the receptors for the anticancer cytokine TRAIL. However, DDAs activate DR4/5 in a novel TRAIL-independent manner. DR4/5 activation by DDAs results from a combination of elevated DR5 expression, disulfide bond-dependent DR4/5 clustering, and localization of DR4/5 to the cell surface. These events occur specifically in EGFR or HER2 overexpressing cancer cells and result in DR4/5 activation of the Caspase 8-Caspase 3 pro-apoptotic cascade. Consistent with this in vitro selectivity, tumor studies demonstrate DDA-induced apoptosis of cancer cells without toxicity to adjacent normal tissues. This project will test the hypothesis that the protein disulfide isomerase AGR2 catalyzes/chaperones native disulfide bonding of EGFR, HER2, DR4, and DR5. We further hypothesize that DDAs inhibit AGR2 enzyme activity and that EGFR and HER2 strongly potentiate DDA actions by competing with DR4/5 for the limited pool of AGR2. Specific Aim 1 is to elucidate the mechanisms by which disulfide bonding within the extracellular domains of DR4/5 restrains their basal pro-apoptotic activity, and demonstrate that genetic or pharmacologic DR5 activation in cancer cells is sufficient to induce tumor regression. Specific Aim 2 is to investigate the mechanisms by which DDAs block AGR2 PDI activity and to demonstrate that DR4/5 activation mediates cancer cell apoptosis in response to ablating AGR2 activity. Specific Aim 3 is to establish the efficacy of DDAs against patient-derived breast tumors and verify that the mechanisms of DDA action in vivo match those identified in vitro. DDA efficacy will be compared with standard therapies in single agent and combination regimens. In summary, this exploratory project will investigate DDAs as a new class of anticancer agents, elucidate a novel AGR2/Death Receptor 4/5 cascade that mediates DDA actions, and establish DDA efficacy against patient-derived models of metastatic and drug-resistant HER2+ breast cancer.

描述 表皮生长因子受体 - 家庭酪氨酸激酶EGFR和HER2在A中过表达 侵略性的，治疗难治性的乳腺癌的比例很大。这包括HER2+肿瘤 已经获得了对HER2特异性单克隆抗体和激酶抑制剂和三阴性的抗性 乳腺癌（TNBC），其中约50％过表达EGFR。选择性杀死EGFR+的代理商 或通过新颖的作用机理HER2+肿瘤可以改善患者的生存 治疗 - 饮食性癌症。我们的团队报告了一种新的抗癌化合物，称为DDA，并与 对EGFR+和HER2+癌症的选择性毒性。发表和初步结果表明 DDA杀死患者衍生的乳腺异种移植肿瘤，没有对实验动物的可检测毒性。 DDAS KILL 癌细胞通过激活死亡受体4和5（DR4/5），这是抗癌细胞因子径的受体。 但是，DDA以一种新颖的轨道独立方式激活DR4/5。 DDA激活DDA的DDA激活 升高的DR5表达，二硫键键依赖性DR4/5聚类的组合以及定位 DR4/5到细胞表面。这些事件专门发生在EGFR或HER2过表达的癌细胞和 导致caspase 8-caspase 3促凋亡级联反应的DR4/5激活。与这个体外一致 选择性，肿瘤研究表明DDA诱导的癌细胞凋亡没有毒性 正常组织。该项目将测试蛋白质二硫化物异构酶AGR2的假设 EGFR，HER2，DR4和DR5的催化剂/伴侣蛋白二硫键。我们进一步假设 DDA抑制AGR2酶活性，EGFR和HER2通过竞争强烈增强DDA的动作 使用有限的AGR2池的DR4/5。特定目的1是阐明二硫化物的机制 在DR4/5的细胞外结构域内粘结限制其基础促凋亡活性，并证明 癌细胞中的遗传学或药理DR5激活足以诱导肿瘤消退。具体的 AIM 2是研究DDA阻断AgR2 PDI活性的机制，并证明了这一点 DR4/5激活响应消融AGR2活性介导癌细胞凋亡。具体目标3是 确定DDA对患者衍生的乳腺肿瘤的功效，并验证DDA的机制是否存在 在体内作用匹配体外鉴定的动作。 DDA功效将与单个的标准疗法进行比较 代理和组合方案。总而言之，这个探索性项目将调查DDA作为新类 抗癌剂，阐明了一种新型的AGR2/死亡受体4/5级联，可介导DDA作用，并 针对转移性和耐药性HER2+乳腺癌的患者衍生模型建立DDA功效。

项目成果

Inhibitors of ERp44, PDIA1, and AGR2 induce disulfide-mediated oligomerization of Death Receptors 4 and 5 and cancer cell death.

ERp44、PDIA1 和 AGR2 抑制剂可诱导二硫键介导的死亡受体 4 和 5 寡聚化以及癌细胞死亡。

• DOI: 10.1016/j.canlet.2022.215604
• 发表时间: 2022
• 期刊: Cancer letters
• 影响因子: 9.7
• 作者: Law,MaryE;Yaaghubi,Elham;Ghilardi,AmandaF;Davis,BradleyJ;Ferreira,RenanB;Koh,Jin;Chen,Sixue;DePeter,SadieF;Schilson,ChristopherM;Chiang,Chi-Wu;Heldermon,CoyD;Nørgaard,Peter;Castellano,RonaldK;Law,BrianK
• 通讯作者: Law,BrianK

Anticancer Agents Derived from Cyclic Thiosulfonates: Structure-Reactivity and Structure-Activity Relationships.

• DOI: 10.1002/cmdc.202200165
• 发表时间: 2022-07-19
• 期刊: ChemMedChem
• 影响因子: 3.4

Disulfide bond-disrupting agents activate the tumor necrosis family-related apoptosis-inducing ligand/death receptor 5 pathway.

二硫键破坏剂激活肿瘤坏死家族相关的凋亡诱导配体/死亡受体 5 通路。

• DOI: 10.1038/s41420-019-0228-9
• 发表时间: 2019
• 期刊: Cell death discovery
• 影响因子: 7
• 作者: Wang,Mengxiong;Law,MaryE;Davis,BradleyJ;Yaaghubi,Elham;Ghilardi,AmandaF;Ferreira,RenanB;Chiang,Chi-Wu;Guryanova,OlgaA;Kopinke,Daniel;Heldermon,CoyD;Castellano,RonaldK;Law,BrianK
• 通讯作者: Law,BrianK

DNMT3A Harboring Leukemia-Associated Mutations Directs Sensitivity to DNA Damage at Replication Forks.

• DOI: 10.1158/1078-0432.ccr-21-2863
• 发表时间: 2022-02-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Venugopal K;Feng Y;Nowialis P;Xu H;Shabashvili DE;Berntsen CM;Kaur P;Krajcik KI;Taragjini C;Zaroogian Z;Casellas Román HL;Posada LM;Gunaratne C;Li J;Dupéré-Richer D;Bennett RL;Pondugula S;Riva A;Cogle CR;Opavsky R;Law BK;Bhaduri-McIntosh S;Kubicek S;Staber PB;Licht JD;Bird JE;Guryanova OA
• 通讯作者: Guryanova OA