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
基本信息
- 批准号:9269177
- 负责人:
- 金额:$ 35.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:1-Phosphatidylinositol 3-KinaseATP phosphohydrolaseAcuteAddressAnabolismAstemizoleAutophagocytosisBioavailableBiological AssayBiological SciencesBreast Cancer CellBreast Cancer PatientBreast Epithelial CellsCell DeathCell LineCellsCleaved cellClinicClinicalComplexComputer SimulationData SetDegradation PathwayDependenceDependencyDiseaseDrug ModelingsDrug SensitizationDrug TargetingDrug resistanceERBB2 geneEndoplasmic ReticulumEpidermal Growth Factor ReceptorEquilibriumErbB Receptor Family ProteinFRAP1 geneFatty AcidsGeneticGenomicsHumanHyperactive behaviorIn VitroLipidsMAPK8 geneMalignant NeoplasmsMammary glandMessenger RNAModelingMusMutateOncogenesOncogenicOralPathway interactionsPatientsPharmaceutical PreparationsPharmacologyPhosphoric Monoester HydrolasesPhosphotransferasesProtein BiosynthesisProteinsReceptor Protein-Tyrosine KinasesRefractoryRefractory DiseaseResistanceStressSystemTestingTherapeuticTimeTrastuzumabUbiquitinXenograft procedureaddictionbasebiological adaptation to stressbreast tumorigenesischolesterol biosynthesisclinically significantcombinatorialdrug candidateeffective therapyefficacy testingendoplasmic reticulum stressin vivoinhibitor/antagonistlapatinibmTOR Signaling Pathwaymalignant breast neoplasmmulticatalytic endopeptidase complexnanomolarnon-oncogenicnoveloutcome forecastoverexpressionpreclinical studypreventproteostasisproteotoxicitypublic health relevancestandard of caresugartargeted treatmenttherapeutic targettumortumor growth
项目摘要
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+癌症的 HER2 靶向治疗的益处有限,并且对于难治性疾病患者不存在治疗选择。利用癌基因诱导的脆弱性作为癌症的治疗策略已成为靶向驱动癌基因的一种有前途的替代方案。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,乳腺上皮细胞中的 HER2 过度表达会诱导内质网 (ER) 中的蛋白毒性应激,而由于 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 来维持适当的蛋白质稳态和存活。因此,靶向 ERAD 可在 EGFR/HER2+ 乳腺癌细胞中选择性诱导蛋白毒性 ER 应激和细胞死亡,包括那些对曲妥珠单抗和拉帕替尼具有从头耐药性和获得性耐药性的细胞。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+ 细胞中的蛋白毒性 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,并且强制不可恢复的蛋白毒性 ER 应激的治疗靶向策略是治疗难治性 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,我们将利用源自患者的异种移植细胞系,在小鼠体内肿瘤生长测定中测试几种新型 ERAD 抑制剂。
项目成果
期刊论文数量(0)
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Kakajan Komurov其他文献
Kakajan Komurov的其他文献
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{{ truncateString('Kakajan Komurov', 18)}}的其他基金
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:
9061645 - 财政年份:2015
- 资助金额:
$ 35.69万 - 项目类别: