Explore the signaling mechanisms of acquired resistance to tyrosine kinase inhibitors in AML
探索 AML 酪氨酸激酶抑制剂获得性耐药的信号机制
基本信息
- 批准号:10589119
- 负责人:
- 金额:$ 40.04万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-03-03 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAcute leukemiaAdultBiochemicalBone DiseasesBone Marrow DiseasesCRISPR screenCell SurvivalCellsClinicClinicalClinical ResearchClinical TreatmentClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsCombined Modality TherapyCytokine ReceptorsDNA Sequence AlterationDataDevelopmentDiseaseDrug resistanceFLT3 geneFamilyGenerationsGenesGenetic ScreeningGoalsHematological DiseaseHematopoiesisHematopoieticKnock-outKnowledgeLeadLearningLibrariesLifeLinkMAP Kinase GeneMEKsMaintenance TherapyMalignant - descriptorMediatorMitogen-Activated Protein KinasesMolecularMolecular AbnormalityMutateMutationPathway interactionsPatientsPharmaceutical PreparationsPlayPositioning AttributePrognosisProtein Tyrosine KinaseProteinsReceptor Protein-Tyrosine KinasesRefractoryRegimenRelapseReportingResistanceRoleSamplingSeriesSignal PathwaySignal TransductionTestingTherapeuticTranslatingTyrosine Kinase InhibitorWNT Signaling Pathwayacquired drug resistanceacute myeloid leukemia cellantagonistbeta catenincell growthclinically relevantgenetic approachin vivoinhibitorinhibitor therapyinsightkinase inhibitorleukemia treatmentloss of functionmembermouse modelnew therapeutic targetnovelresistance mechanismresponsesmall moleculesuccesstargeted treatmenttranslational potential
项目摘要
Explore the signaling mechanisms of acquired resistance to tyrosine kinase inhibitors in AML
Abstract
Acute myeloid leukemia (AML) is a malignant hematopoietic disease and the most common type of acute
leukemia in adults. One major obstacle to greater success with target therapy of leukemia is drug resistance.
The mechanisms underlying drug resistance in AML are poorly understood. FLT3 is a cytokine receptor which
belongs to the receptor tyrosine kinase (RTK) class III. Activating mutations in FMS-like tyrosine kinase 3
(FLT3) are now recognized as the most common molecular abnormality in AML and FLT3ITD mutations are
found in nearly 30% of AML patients. Quizartinib (AC220) is a potent and selective second-generation inhibitor
of FLT3. It is in clinical trials for the treatment of relapsed or refractory FLT3ITD positive and negative AML
patients and as maintenance therapy. Remarkably, those clinical trials have showed very promising result.
However, drug resistance to AC220 has also been reported through the early clinical studies.
To understand the underlying mechanisms of drug resistance to AC220, we undertook an unbiased approach
with a novel CRISPR pooled library to screen new genes whose loss of function confers resistance to AC220.
In our screen, we identified SPRY3, an intracellular inhibitor of RTK signaling, and GSK3, a canonical Wnt
signaling antagonist, and demonstrated that re-activation of downstream RTK/Ras/ERK and Wnt signaling as
major mechanisms of resistance to the FLT3 inhibitor. Furthermore, we also confirmed our findings in primary
AML patient samples. We demonstrated that the expression level of SPRY3 and GSK3A is dramatically
reduced in AC220 resistant AML samples and SPRY3 deleted primary AML cells are resistant to AC220.
Additionally, we treated SPRY3 and GSK3 knockout AML cells with a potent MAP kinase inhibitor and β-
catenin inhibitor respectively, demonstrated that both inhibitors re-sensitized AML cells to AC220. Intriguingly,
we found that expression of SPRY3 is greatly reduced in GSK3 knockout AML cells, which positioned SPRY3
downstream of GSK3 in the resistance pathway.
In this proposal, we hypothesize that Sprouty (SPRY) and GSK3 play critical roles in the response to
tyrosine kinase inhibitor in AML. The Ras/MEK/ERK and Wnt pathways regulated by SPRY3 and GSK3
are important for the acquired drug resistance in AML. Next, we will perform a series comprehensive study
to explore novel downstream effectors/ interacting partners of SPRY3 and GSK3 in AMLs and the molecular
mechanisms of their action. Furthermore, we will examine the possibility to translate our findings into new
clinical therapies.
Taken together, our study identified novel genes whose loss of function confers resistance to a selective FLT3
inhibitor and revealed the underlying mechanism, thereby providing new insight into signaling pathways that
contribute to the acquired resistance in AML. The knowledge learned may lead to the development of more
efficient combined therapeutic avenues for AML.
探讨AML对酪氨酸激酶抑制剂获得性耐药的信号机制
摘要
急性髓性白血病(AML)是一种恶性造血系统疾病,是最常见的急性白血病类型。
成人白血病白血病靶向治疗取得更大成功的一个主要障碍是耐药性。
人们对急性粒细胞白血病耐药的机制知之甚少。FLT 3是细胞因子受体,
属于受体酪氨酸激酶(RTK)III类。FMS样酪氨酸激酶3的激活突变
FLT 3突变是AML中最常见的分子异常,FLT 3 ITD突变是AML中最常见的分子异常。
在近30%的AML患者中发现。Quizartinib(AC 220)是一种强效、选择性的第二代抑制剂
在FLT 3它正在临床试验中用于治疗复发性或难治性FLT 3 ITD阳性和阴性AML
患者和维持治疗。值得注意的是,这些临床试验显示出非常有希望的结果。
然而,通过早期临床研究也报告了对AC 220的耐药性。
为了了解AC 220耐药的潜在机制,我们采用了一种无偏倚的方法,
利用一个新的CRISPR汇集文库来筛选功能丧失导致对AC 220产生抗性的新基因。
在我们的筛选中,我们鉴定了SPRY 3,一种RTK信号传导的细胞内抑制剂,和GSK 3,一种典型的Wnt
信号拮抗剂,并证明下游RTK/Ras/ERK和Wnt信号转导的重新激活,
对FLT 3抑制剂耐药的主要机制。此外,我们还证实了我们的研究结果,
AML患者样品。我们证明SPRY 3和GSK 3A的表达水平显著地降低,
在AC 220抗性AML样品中,SPRY 3缺失的原代AML细胞对AC 220具有抗性。
此外,我们用有效的MAP激酶抑制剂和β-
连环蛋白抑制剂的作用,证明两种抑制剂都使AML细胞对AC 220重新敏感。有趣的是,
我们发现SPRY 3在GSK 3敲除的AML细胞中表达大大降低,这使得SPRY 3
在抗性途径中的GSK 3下游。
在这个提议中,我们假设Sprouty(SPRY)和GSK 3在对
酪氨酸激酶抑制剂。SPRY 3和GSK 3对Ras/MEK/ERK和Wnt通路的调控
对于AML的获得性耐药性很重要。接下来,我们将进行一系列的综合研究,
探索AML中SPRY 3和GSK 3的新型下游效应物/相互作用伴侣,
他们的行动机制。此外,我们将研究将我们的发现转化为新的
临床治疗。
总之,我们的研究确定了新的基因,其功能的丧失赋予了对选择性FLT 3的抗性。
抑制剂,并揭示了潜在的机制,从而提供了新的见解信号通路,
有助于AML的获得性耐药。学到的知识可能会导致更多的发展
AML的有效联合治疗途径。
项目成果
期刊论文数量(0)
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Jian Huang其他文献
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{{ truncateString('Jian Huang', 18)}}的其他基金
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GSK3/PPAR-/线粒体自噬通路在调节造血中的作用
- 批准号:
10545088 - 财政年份:2022
- 资助金额:
$ 40.04万 - 项目类别:
The role of GSK3/PPAR-/mitophagy pathway in regulating hematopoia
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- 批准号:
10365005 - 财政年份:2022
- 资助金额:
$ 40.04万 - 项目类别:
Explore the signaling mechanisms of acquired resistance to tyrosine kinase inhibitors in AML
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