Development of a first-in-class mEGFR dimerization inhibitor

开发一流的 mEGFR 二聚化抑制剂

基本信息

批准号：
10435117
负责人：
THEODORE S LAWRENCE
金额：
$ 35.1万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2020-04-03 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10435117
关键词：
Ablation Address Adenoviruses Affect Age Antioxidants Bypass Cancer Model Cell Death Cell Line Cell Survival Cell membrane Cells Cetuximab Client Clustered Regularly Interspaced Short Palindromic Repeats Co-Immunoprecipitations Consequentialism Cystine DNA Damage Data Development Dimerization Dose Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Exhibits Free Radical Scavengers Glucose Glutamates Glutathione Goals HCT116 Cells Human KRAS2 gene KRASG12D Knock-out Lung Mediating Membrane Membrane Transport Proteins Metabolic stress Modeling Mus Mutation Nutrient Oral Oxidative Stress Pancreas Pancreatic Intraepithelial Neoplasia Pathway interactions Patients Permeability Peroxidases Pharmaceutical Preparations Phosphotransferases Play Proteins Proto-Oncogene Proteins c-akt Resistance Role Safety Scaffolding Protein Small Interfering RNA Solid Neoplasm Therapeutic Therapeutic Effect Tissues Transfection Transgenic Mice Tyrosine Kinase Inhibitor Viral Xenograft procedure adenoma aerobic glycolysis base cancer cell cell killing conditional knockout cytotoxic experimental study fluorodeoxyglucose positron emission tomography glucose uptake glutathione peroxidase inhibitor kinase inhibitor mouse model mutant novel novel therapeutics overexpression prevent protein expression reactive oxygen intermediate resistance mutation response scaffold small hairpin RNA tumor tumorigenesis uptake

项目摘要

Project Summary/Abstract The KRAS mutation (mtKRAS) occurs in approximately 25% of all human tumors and confers resistance to EGFR tyrosine kinase inhibitors (TKI). Targeting KRAS mutations with drugs has been challenging. We are developing DGD-1202 a specific degrader, not an inhibitor, of activated EGFR kinase that exhibits profound activity against mtKRAS-driven murine tumor models. Our data indicate that degradation of activated EGFR without affecting mtKRAS levels could be a novel therapy for TKI-resistant mtKRAS-driven tumors. We hypothesize that in such wtEGFR/mtKRAS tumor types, kinase-independent roles of EGFR are vital for cell survival. Therefore, degradation of activated EGFR is sufficient to kill cells, including mtKRAS expressing cells. The overall goal of our study is to confirm the efficacy and mechanism of action of DGD-1202. Accordingly, the three specific aims of this proposal are as follows. In Aim 1, we will determine the kinase-independent roles of EGFR protein in mtKRAS-driven tumors. The ablation of EGFR by siRNA or shRNA kills both EGFR-driven or mtKRAS expressing cells. This indicates that EGFR protein plays an essential role in cell survival, independent of its kinase functions. We hypothesize that kinase-dead (KD) EGFR protein expression will rescue cell death induced by EGFR ablation in these cells. In this aim, we will investigate if kinase-dead EGFR can promote cell survival and rescue DGD-1202 mediated cell death. In Aim 2, we will elucidate the mechanisms by which DGD-1202 induced EGFR degradation overcomes mtKRAS mediated TKI resistance. EGFR protein plays important scaffolding functions, and its ablation results in the loss of membrane transporters such as xCT and SGLT1. Loss of these transporters limits cellular uptake of cystine and glucose, respectively, thus reducing the synthesis of glutathione peroxidase, a key free radical scavenger. In this aim, we will investigate the effects of DGD-1202 induced EGFR degradation on xCT and SGLT1 in mtKRAS-driven cancer cells and its effect on the accumulation of reactive oxygen intermediates. Based on our preliminary data, we hypothesize that DGD-1202 will reduce xCT and SGLT1 protein levels in wtEGFR cells but have minimal effect in KD EGFR expressing cells, where DGD-1202 does not degrade EGFR. Finally, in Aim 3, we will assess the efficacy of DGD-1202 in a panel of mtKRAS-driven, EGFR TKI-resistant xenograft, and transgenic mouse models. Our preliminary data indicate the robust single-agent activity of DGD-1202 in several mtKRAS-driven cancer models. In this aim, we will determine the dose and exposure-response profiles. We will also determine the effect of DGD-1202 treatment on long-term survival. This approach will target a broad spectrum of patients and offer a therapeutic option for both treatment-naive and EGFR-TKI resistant mtKRAS-driven tumors.

项目摘要/摘要 KRAS突变（mtkras）发生在所有人类肿瘤的大约25％中，并赋予对 EGFR酪氨酸激酶抑制剂（TKI）。用药物靶向KRAS突变一直具有挑战性。我们是开发DGD-12202活化EGFR激酶的特定降解器，而不是抑制剂，它表现出深刻针对MTKRAS驱动的鼠肿瘤模型的活性。我们的数据表明激活的EGFR降解不影响mtkras水平，可能是对TKI耐MTKRAS驱动肿瘤的一种新型疗法。我们假设在这样的WTEGFR/mtkras肿瘤类型中，EGFR的激酶独立的作用对于细胞至关重要生存。因此，活化的EGFR的降解足以杀死包括表达细胞的mtkras。我们研究的总体目标是确认DGD-12202的作用的功效和机制。因此，该提案的三个具体目标如下。在AIM 1中，我们将确定与激酶无关的角色 MTKRAS驱动的肿瘤中的EGFR蛋白。 siRNA或shRNA的EGFR烧蚀杀死了EGFR驱动的两个或表达细胞的mtkras。这表明EGFR蛋白在细胞存活中起着至关重要的作用其激酶功能。我们假设激酶死亡（KD）EGFR蛋白表达将挽救细胞死亡这些细胞中的EGFR消融诱导。在此目标中，我们将调查激酶已故EGFR是否可以促进细胞生存和救援DGD-12202介导的细胞死亡。在AIM 2中，我们将阐明该机制 DGD-12202诱导的EGFR降解克服了MTKRAS介导的TKI耐药性。 EGFR蛋白发挥重要的脚手架功能及其消融导致膜转运蛋白（例如XCT和）的损失 SGLT1。这些转运蛋白的损失分别限制了胱氨酸和葡萄糖的细胞摄取，从而降低了谷胱甘肽过氧化物酶的合成，这是一种关键的自由基清除剂。在此目标中，我们将研究 DGD-1202在mtkras驱动的癌细胞中诱导XCT和SGLT1上的EGFR降解及其对其对活性氧中间体的积累。根据我们的初步数据，我们假设DGD-12202 将降低WTEGFR细胞中的XCT和SGLT1蛋白水平，但对KD EGFR表达细胞的影响最小，其中DGD-12202不会降解EGFR。最后，在AIM 3中，我们将评估DGD-1202的功效 MTKRAS驱动的面板，EGFR TKI耐药异种移植物和转基因小鼠模型。我们的初步数据表明在几种mTKRAS驱动的癌症模型中，DGD-12202的鲁棒单药活性。在这个目标中我们将确定剂量和暴露响应曲线。我们还将确定DGD-12202的效果长期生存的治疗。这种方法将针对广泛的患者，并提供治疗性抗治疗方法和EGFR-TKI抗MTKRAS驱动的肿瘤的选择。