Targeting the HGF-MET-TWIST1 pathway to overcome EGFR TKI resistance
Targeting the HGF-MET-TWIST1 pathway to overcome EGFR TKI resistance
批准号:
10390353
负责人:
Timothy F. Burns
金额:
$36.28万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-08-01 至 2025-04-30
关键词:
ApoptosisApoptoticBCL2L11 geneCell LineClinicClinicalDataDevelopmentDrug resistanceEpidermal Growth FactorEpidermal Growth Factor ReceptorEpidermal Growth Factor Receptor Tyrosine Kinase InhibitorEpithelialErlotinibFDA approvedGenerationsHGF geneHarmineHumanIn VitroLeadLinkMalignant neoplasm of lungMediatingMediator of activation proteinMesenchymalModelingMusNon-Small-Cell Lung CarcinomaPathway interactionsPatientsPharmacologyPhenotypePhosphorylationPositioning AttributePost-Translational Protein ProcessingProto-Oncogene Proteins c-aktPublishingReportingRepressionResistanceRoleSignal TransductionTWIST1 geneTestingTherapeuticTimeTreatment EfficacyTyrosine Kinase InhibitorWild Type MouseXenograft procedureclinically significantefficacy evaluationefficacy testingexperimental studyfunctional outcomesin vivoin vivo Modelinhibitorlung tumorigenesismouse modelmutantnew therapeutic targetnext generationnovelnovel therapeuticspatient derived xenograft modelpre-clinicalpreventresponsesenescencetargeted treatmenttranscription factortranslational impacttumortumorigenesis
中文摘要
表皮生长因子受体突变体(MT)非小细胞肺癌(NSCLC),
最初对EGFR酪氨酸激酶抑制剂(TKIs)有很高的应答率,然而,耐药性是不可避免的。
HGF-MET通路激活与上皮-间充质转化转录因子的表达
间充质表型是EGFR TKI耐药的常见机制。我们已经确定了
肝细胞生长因子-MET-Twist1轴作为一种新的靶向信号轴,可能解释
对包括奥西美替尼在内的EGFR TKIs的初始耐药和获得性耐药。我们公布的数据显示,
EMT-Tf、Twist1在EGFR Mt肿瘤发生中的作用及其在体外和体内介导的EGFR TKI耐药
体内通过抑制细胞凋亡而发挥作用。以Twist1为靶点,无论是从基因上还是药物上,我们都是一流的
Twist1抑制剂,骆驼蓬碱使EGFR mt NSCLC对EGFR TKIs重新增敏。我们的初步数据表明
HGF增加Twist1的表达,扭转抑制可逆转HGF-MET介导的EGFR TKI
体外抗药性。因此,Twist1可能是连接这些通路的关键靶点。
中心假说:HGF-MET介导的Twist1诱导可抑制细胞凋亡和EGFR
在EGFR mt NSCLC中,TKI耐药可通过抑制Twist1来克服。我们将检验这一假设
在以下具体目标中:
目的1:探讨肝细胞生长因子依赖的Twist1诱导表皮生长因子受体的机制及临床意义
突变型NSCLC。假设:HGF通过磷酸化导致Twist1表达和活性增加
ERK和/或AKT(目标1a)。我们进一步假设HGF-MET的激活与
Twist1在EGFR TKI从头开始和获得性耐药设置中的表达和对EGFR TKI的低反应
住院病人(目标1b)
目的:阐明HGF-Twist1介导的EGFR TKI耐药机制。假设:Twist1
通过介导HGF-MET依赖的EGFR TKI在新生和获得性耐药中的作用
体外(Aim 2a)和体内(Aim 2b-c)抑制细胞凋亡。
目的3:评价Twist1抑制剂骆驼蓬碱对抗HGF-MET诱导的EGFR TKI的疗效
抵抗。假设:用骆驼蓬碱联合奥西莫替尼靶向Twist1将克服HGF-
在体外和体内获得性抗性设置中,诱导抗性以及MET驱动抗性。
转译影响:在奥西美替尼进展后,没有FDA批准的靶向治疗。我们
在确定Twist1是HGF-MET依赖的EGFR TKI耐药的中介物和
治疗EGFR TKI耐药的新靶点。
英文摘要
Epidermal Growth Factor Receptor (EGFR) mutant (mt) non-small cell lung cancer (NSCLC),
initially has a high response rate to EGFR tyrosine kinase inhibitors (TKIs), however, resistance is inevitable.
HGF-MET pathway activation and an epithelial-mesenchymal transition (EMT) transcription factor (TF) induced
mesenchymal phenotype are commonly observed mechanisms of EGFR TKI resistance. We have identified the
hepatocyte growth factor (HGF)-MET-TWIST1 axis as a novel targetable signaling axis that may account for
both de novo and acquired resistance to EGFR TKIs including osimertinib. Our published data showed that the
EMT-TF, TWIST1 is required for EGFR mt tumorigenesis and can mediated EGFR TKI resistance in vitro and in
vivo through suppression of apoptosis. Targeting TWIST1, genetically or pharmacologically with our first-in-class
TWIST1 inhibitor, harmine resensitized EGFR mt NSCLC to EGFR TKIs. Our preliminary data demonstrate that
HGF increases TWIST1 expression and that TWIST inhibition can reverse HGF-MET mediated EGFR TKI
resistance in vitro. Therefore, TWIST1 maybe the critical targetable node that connects these pathways.
Central hypothesis: HGF-MET mediated induction of TWIST1 leads to the suppression of apoptosis and EGFR
TKI resistance in EGFR mt NSCLC, which can be overcome with TWIST1 inhibition. We will test this hypothesis
in the following Specific Aims:
Aim 1: Determine the mechanism and clinical significance of HGF-dependent TWIST1 induction in EGFR
mutant NSCLC. Hypothesis: HGF leads to increased TWIST1 expression and activity through phosphorylation
by ERK and/or AKT (Aim 1a). We further hypothesize that HGF-MET activation correlates with increased
TWIST1 expression and poor response to EGFR TKIs in the EGFR TKI de novo and acquired resistance setting
in patients (Aim 1b)
Aim 2: Elucidate the mechanism of HGF-TWIST1-mediated EGFR TKI resistance. Hypothesis: TWIST1
mediates HGF-MET dependent EGFR TKI resistance in both de novo and acquired resistance through
suppression of apoptosis in vitro (aim 2a) and in vivo (aim 2b-c).
Aim 3: Evaluate the efficacy of the TWIST1 inhibitor, harmine to overcome HGF-MET induced EGFR TKI
resistance. Hypothesis: Targeting TWIST1 with harmine in combination with osimertinib will overcome HGF-
induced resistance as well as MET driven resistance in the acquired resistance setting in vitro and in vivo.
Translational Impact: There are no FDA approved targeted therapies after progression on osimertinib. We
are uniquely positioned to identify TWIST1 as a mediator of HGF-MET-dependent EGFR TKI resistance and a
novel therapeutic target for the treatment of EGFR TKI resistance.
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Targeting the HGF-MET-TWIST1 pathway to overcome EGFR TKI resistance
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批准号:10605174
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项目类别:
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资助金额:$35.64万
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财政年份:2020
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负责人:Timothy F. Burns
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依托单位:
海外基金