Targeting the HGF-MET-TWIST1 pathway to overcome EGFR TKI resistance

靶向 HGF-MET-TWIST1 通路克服 EGFR TKI 耐药

基本信息

批准号：
10390353
负责人：
Timothy F. Burns
金额：
$ 36.28万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10390353
关键词：
Apoptosis Apoptotic BCL2L11 gene Cell Line Clinic Clinical Data Development Drug resistance Epidermal Growth Factor Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epithelial Erlotinib FDA approved Generations HGF gene Harmine Human In Vitro Lead Link Malignant neoplasm of lung Mediating Mediator of activation protein Mesenchymal Modeling Mus Non-Small-Cell Lung Carcinoma Pathway interactions Patients Pharmacology Phenotype Phosphorylation Positioning Attribute Post-Translational Protein Processing Proto-Oncogene Proteins c-akt Publishing Reporting Repression Resistance Role Signal Transduction TWIST1 gene Testing Therapeutic Time Treatment Efficacy Tyrosine Kinase Inhibitor Wild Type Mouse Xenograft procedure clinically significant efficacy evaluation efficacy testing experimental study functional outcomes in vivo in vivo Model inhibitor lung tumorigenesis mouse model mutant new therapeutic target next generation novel novel therapeutics patient derived xenograft model pre-clinical prevent response senescence targeted treatment transcription factor translational impact tumor tumorigenesis

项目摘要

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.

表皮生长因子受体（EGFR）突变体（mt）非小细胞肺癌（NSCLC），最初对EGFR酪氨酸激酶抑制剂（TKI）有较高的反应率，但耐药性是不可避免的。 HGF-MET 通路激活和上皮间质转化 (EMT) 转录因子 (TF) 诱导间充质表型是 EGFR TKI 耐药的常见机制。我们已经确定了肝细胞生长因子 (HGF)-MET-TWIST1 轴作为一种新型靶向信号轴，可能解释对包括奥希替尼在内的 EGFR TKI 产生耐药性和获得性耐药。我们公布的数据显示， EMT-TF、TWIST1 是 EGFR mt 肿瘤发生所必需的，并且可以在体外和体内介导 EGFR TKI 耐药性体内通过抑制细胞凋亡。使用我们的一流产品从遗传或药理学角度针对 TWIST1 TWIST1 抑制剂去氢骆驼蓬碱使 EGFR mt NSCLC 对 EGFR TKI 重新敏感。我们的初步数据表明 HGF 增加 TWIST1 表达，抑制 TWIST 可以逆转 HGF-MET 介导的 EGFR TKI 体外耐药性。因此，TWIST1可能是连接这些通路的关键目标节点。中心假设：HGF-MET 介导的 TWIST1 诱导导致细胞凋亡和 EGFR 的抑制 EGFR mt NSCLC 中的 TKI 耐药性可以通过 TWIST1 抑制来克服。我们将检验这个假设具体目标如下：目标 1：确定 HGF 依赖性 TWIST1 诱导 EGFR 的机制和临床意义突变非小细胞肺癌。假设：HGF 通过磷酸化导致 TWIST1 表达和活性增加通过 ERK 和/或 AKT（目标 1a）。我们进一步假设 HGF-MET 激活与增加 EGFR TKI 新生和获得性耐药环境中 TWIST1 表达和对 EGFR TKI 的不良反应在患者中（目标 1b）目标 2：阐明 HGF-TWIST1 介导的 EGFR TKI 耐药机制。假设：TWIST1 通过介导 HGF-MET 依赖性 EGFR TKI 耐药性，无论是从头耐药还是获得性耐药体外（目标 2a）和体内（目标 2b-c）抑制细胞凋亡。目标 3：评估 TWIST1 抑制剂去氢骆驼蓬碱克服 HGF-MET 诱导的 EGFR TKI 的功效反抗。假设：用去氢骆驼蓬碱联合奥希替尼靶向 TWIST1 将克服 HGF- 在体外和体内的获得性耐药环境中诱导耐药性以及 MET 驱动的耐药性。转化影响：尚无 FDA 批准的奥希替尼治疗进展后的靶向疗法。我们具有独特的定位，可以将 TWIST1 确定为 HGF-MET 依赖性 EGFR TKI 耐药性的调节剂，并且治疗 EGFR TKI 耐药的新治疗靶点。