Characterizing Regulatory Mechanisms Underlying Drug Resistance in Breast Cancer Using Keratin 19
使用角蛋白 19 表征乳腺癌耐药性背后的调节机制
基本信息
- 批准号:10358875
- 负责人:
- 金额:$ 47.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-06-02 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectBindingBiochemicalBiologicalBiological AssayBreast Cancer CellBreast Cancer PatientCDK4 geneCancer PatientCell CycleCell LineCell NucleusCell ProliferationCellsCellular biologyConsensusCoupledCytoskeletal ProteinsDataDrug resistanceEstrogen receptor positiveEventExhibitsFilamentFluorescence Recovery After PhotobleachingGene ExpressionGenesGoalsGrowthKeratinKeratin-19KnowledgeMalignant NeoplasmsMediatingMolecularMovementMutateNuclearPathway interactionsPatientsPhenotypePhosphotransferasesPredispositionProcessPrognostic MarkerProteinsResearchResistanceResistance developmentResourcesRoleSignal PathwaySignal TransductionSiteStudentsTechnologyTestingTrainingVertebral columnWorkadvanced breast cancerbasecancer subtypescancer typecombatcyclin D3designdiagnostic biomarkerdifferential expressionexperimental studyhormone receptor-positivehormone sensitivityhormone therapyin vivoinhibitormalignant breast neoplasmmouse modelmutantnew therapeutic targetnovelnucleocytoplasmic transportpredictive markerpreventresponseresponse biomarkerscaffoldsmall molecule inhibitortargeted biomarkertargeted treatmenttherapeutically effectivetranscription factortranscriptome sequencingtumortumor growth
项目摘要
PROJECT SUMMARY
Drug resistance continues to be the major limiting factor in achieving cures for cancer patients. In breast
cancer, cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors have been approved recently to treat patients
with advanced estrogen receptor-positive tumors. However, most patients exhibit resistance due to a lack of
predictive biomarker. Understanding the molecular basis underlying drug resistance is required to provide a
critical breakthrough in identifying a predictive biomarker and developing effective therapeutic strategies.
Based on our previous work and preliminary data, we propose that a cytoskeletal protein keratin 19 (K19),
which currently serves as one of the most reliable diagnostic and prognostic markers, regulates signaling
events to impact resistance against CDK4/6 inhibitors. We found that K19 binds to and inhibits a
multifunctional kinase GSK to stabilize a CDK4/6 partner cyclin D3 in breast cancer cells. K19-GSK3
interaction was associated with decreased accumulation of GSK3 in the nucleus that is crucial to GSK3
function. Moreover, K19 promoted proliferation and maintained the sensitivity of cells to CDK4/6 inhibitors. We
hypothesize that cyclin D3 stabilized by K19-dependent inhibition of GSK3 causes tumors to become
dependent on the CDK4/6 pathway for growth and sensitizes them to CDK4/6 inhibitors. At the molecular level,
we surmise that K19 filaments serve as cytoplasmic scaffolds for GSK3 to prevent its entry into the nucleus
where it phosphorylates cyclin D3 for degradation. To address our hypotheses, we propose to 1) determine
K19 effects on the GSK3 signaling network, 2) characterize the interaction between K19 and GSK3, and 3)
determine the impact of K19 on drug resistance and tumor growth. To this end, in Aim 1, we will identify
upstream regulators of K19-GSK3 interaction as well as GSK3 targets whose activities affect K19-
dependent phenotypes. In Aim 2, GSK3-binding deficient K19 mutant will be characterized to determine how
K19 interacts with GSK3 and affects the nuclear entry of GSK3. In Aim 3, we will assess how K19 affects
sensitivities of various breast cancer subtypes to CDK4/6 inhibitors and test the role of K19 and GSK3 on the
sensitivity of tumors to a CDK4/6 inhibitor in vivo. Upon successful completion, the knowledge gained from the
study can help design new drugs targeting K19-dependent signaling pathways, establish K19 as a predictive
biomarker for response to CDK4/6 inhibitors, and develop effective therapeutic strategies to combat drug
resistance.
项目摘要
耐药性仍然是实现癌症患者治愈的主要限制因素。乳腺
细胞周期蛋白依赖性激酶4和6(CDK4/6)抑制剂最近已被批准用于治疗癌症患者
患有晚期雌激素受体阳性肿瘤然而,大多数患者表现出抵抗,由于缺乏
预测性生物标志物。了解耐药性背后的分子基础是必要的,
在鉴定预测性生物标志物和开发有效的治疗策略方面取得了重大突破。
基于我们以前的工作和初步数据,我们提出细胞骨架蛋白角蛋白19(K19),
目前作为最可靠的诊断和预后标志物之一,
影响CDK4/6抑制剂耐药性的事件。我们发现K19结合并抑制了
在乳腺癌细胞中,多功能激酶GSK-1用于稳定CDK4/6伴侣细胞周期蛋白D3。公司简介
相互作用与细胞核中GSK 3 β的积累减少有关,而细胞核中GSK 3 β的积累对GSK 3 β的表达至关重要。
功能此外,K19促进细胞增殖并维持细胞对CDK4/6抑制剂的敏感性。我们
假设细胞周期蛋白D3通过依赖K19的GSK3抑制而稳定,
依赖于CDK4/6途径生长,并使它们对CDK4/6抑制剂敏感。在分子水平上,
我们推测,K19纤维作为细胞质支架,阻止GSK 3进入细胞核,
在那里它磷酸化细胞周期蛋白D3进行降解。为了解决我们的假设,我们建议1)确定
K19对GSK3 β信号网络的影响,2)表征K19和GSK3 β之间的相互作用,以及3)
确定K19对耐药性和肿瘤生长的影响。为此,在目标1中,我们将确定
K19-GSK3 β相互作用的上游调节因子以及其活性影响K19-GSK3 β相互作用的GSK3 β靶标。
依赖表型在目标2中,将表征GSK3 β结合缺陷型K19突变体以确定如何在细胞内表达GSK3 β。
K19与GSK 3 β相互作用并影响GSK 3 β的核进入。在目标3中,我们将评估K19如何影响
不同乳腺癌亚型对CDK4/6抑制剂的敏感性,并测试K19和GSK3在乳腺癌中的作用。
体内肿瘤对CDK4/6抑制剂的敏感性。成功完成后,从
这项研究可以帮助设计靶向K19依赖性信号通路的新药,建立K19作为预测
CDK4/6抑制剂反应的生物标志物,并开发有效的治疗策略,以对抗药物
阻力
项目成果
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