Exploiting proteotoxic stress in therapy-refractory HER2+ breast cancers

利用蛋白毒性应激治疗难治性 HER2 乳腺癌

• 批准号: 9269177
• 负责人: Kakajan Komurov
• 金额: $ 35.69万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269177
• 关键词: 1-Phosphatidylinositol 3-Kinase; ATP phosphohydrolase; Acute; Address; Anabolism; Astemizole; Autophagocytosis; Bioavailable; Biological Assay; Biological Sciences; Breast Cancer Cell; Breast Cancer Patient; Breast Epithelial Cells; Cell Death; Cell Line; Cells; Cleaved cell; Clinic; Clinical; Complex; Computer Simulation; Data Set; Degradation Pathway; Dependence; Dependency; Disease; Drug Modelings; Drug Sensitization; Drug Targeting; Drug resistance; ERBB2 gene; Endoplasmic Reticulum; Epidermal Growth Factor Receptor; Equilibrium; ErbB Receptor Family Protein; FRAP1 gene; Fatty Acids; Genetic; Genomics; Human; Hyperactive behavior; In Vitro; Lipids; MAPK8 gene; Malignant Neoplasms; Mammary gland; Messenger RNA; Modeling; Mus; Mutate; Oncogenes; Oncogenic; Oral; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phosphoric Monoester Hydrolases; Phosphotransferases; Protein Biosynthesis; Proteins; Receptor Protein-Tyrosine Kinases; Refractory; Refractory Disease; Resistance; Stress; System; Testing; Therapeutic; Time; Trastuzumab; Ubiquitin; Xenograft procedure; addiction; base; biological adaptation to stress; breast tumorigenesis; cholesterol biosynthesis; clinically significant; combinatorial; drug candidate; effective therapy; efficacy testing; endoplasmic reticulum stress; in vivo; inhibitor/antagonist; lapatinib; mTOR Signaling Pathway; malignant breast neoplasm; multicatalytic endopeptidase complex; nanomolar; non-oncogenic; novel; outcome forecast; overexpression; preclinical study; prevent; proteostasis; proteotoxicity; public health relevance; standard of care; sugar; targeted treatment; therapeutic target; tumor; tumor growth

 DESCRIPTION (provided by applicant): Benefits of HER2-targeted therapy in HER2+ cancers are limited due to significant de novo and acquired resistance, and no therapy options exist for patients with refractory disease. Exploiting oncogene-induced vulnerabilities as a therapeutic strategy in cancers has emerged as a promising alternative to targeting of driver oncogenes. Our preliminary in silico analyses of clinical datasets and in vitro analyses on cell lines have revealed that HER2 overexpression in the mammary epithelial cells induces proteotoxic stress in the endoplasmic reticulum (ER), which is relieved in HER2+ breast cancer cells due to specific overexpression of the ER-associated degradation (ERAD) complex. We have found that HER2+ breast cancer cells are acutely dependent on ERAD to maintain proper protein homeostasis and survival. Accordingly, targeting of ERAD induces proteotoxic ER stress and cell death selectively in EGFR/HER2+ breast cancer cells, including those with de novo and acquired resistance to trastuzumab and lapatinib. In addition, we have found that combinatorial targeting of ERAD and adaptive ER stress response machinery can synergize in the induction of proteotoxic ER stress and cell death in drug- resistant HER2+ cells. Based on these results, we propose that oncogenic HER2-induced proteotoxic ER stress is a clinically significant vulnerability, and that the therapeutic targeting strategies to force irrecoverable proteotoxic ER stress are an effective approach against therapy-refractory HER2+ breast cancers. In this proposal, we propose to 1) identify the mechanisms of addiction of HER2+ cells to ERAD, 2) identify novel potent combinatorial strategies of maximizing oncogenic ER stress, and 3) test in vivo efficacy of inducing oncogenic proteotoxic stress in drug-resistant breast cancers. In Aim 3, we will test several novel inhibitors of ERAD in in vivo tumor growth assays in mice making use of patient- derived xenograft lines.

 描述（由申请人提供）：由于显着的新发耐药和获得性耐药，HER2 靶向治疗在 HER2+ 癌症中的益处有限，并且对于患有难治性疾病的患者不存在利用癌基因诱导的脆弱性作为癌症治疗策略的治疗选择。我们对临床数据集的初步计算机分析和对细胞系的体外分析表明，HER2 过度表达是靶向驱动癌基因的一种有前途的替代方案。乳腺上皮细胞在内质网 (ER) 中诱导蛋白毒性应激，由于 ER 相关降解 (ERAD) 复合物的特异性过度表达，这种应激在 HER2+ 乳腺癌细胞中得到缓解。我们发现 HER2+ 乳腺癌细胞严重依赖 ERAD。从而维持适当的蛋白质稳态和存活，因此，靶向 ERAD 可选择性诱导 EGFR/HER2+ 乳腺中的蛋白毒性 ER 应激和细胞死亡。癌细胞，包括对曲妥珠单抗和拉帕替尼产生耐药性和获得性耐药的癌细胞。此外，我们发现 ERAD 和适应性 ER 应激反应机制的组合靶向可以协同诱导耐药 HER2+ 中的蛋白毒性 ER 应激和细胞死亡。基于这些结果，我们提出致癌 HER2 诱导的蛋白毒性 ER 应激是临床上显着的脆弱性，并且治疗靶向策略迫使其不可恢复。蛋白毒性 ER 应激是对抗难治性 HER2+ 乳腺癌的有效方法。在本提案中，我们建议 1) 确定 HER2+ 细胞对 ERAD 成瘾的机制，2) 确定最大化致癌 ER 应激的新型有效组合策略，3)。 ）测试在耐药乳腺癌中诱导致癌蛋白毒性应激的体内功效。在目标 3 中，我们将测试几种新型 ERAD 抑制剂。利用源自患者的异种移植物系对小鼠进行体内肿瘤生长测定。