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

靶向 HGF-MET-TWIST1 通路克服 EGFR TKI 耐药

• 批准号: 10224741
• 负责人: TIMOTHY F BURNS
• 金额: $ 35.8万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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/10224741
• 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/antagonist; 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

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）