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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.

项目概要/摘要 KRAS 突变 (mtKRAS) 发生在大约 25% 的人类肿瘤中，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-1202，一种活化 EGFR 激酶的特异性降解剂，而不是抑制剂，具有深远的影响针对 mtKRAS 驱动的小鼠肿瘤模型的活性。我们的数据表明激活的 EGFR 的降解在不影响 mtKRAS 水平的情况下，可能是一种治疗 TKI 耐药性 mtKRAS 驱动肿瘤的新疗法。我们假设在这种 wtEGFR/mtKRAS 肿瘤类型中，EGFR 的激酶独立作用对于细胞至关重要生存。因此，活化的 EGFR 的降解足以杀死细胞，包括表达 mtKRAS 的细胞。我们研究的总体目标是确认 DGD-1202 的功效和作用机制。据此，该提案的三个具体目标如下。在目标 1 中，我们将确定激酶独立的作用 mtKRAS 驱动的肿瘤中 EGFR 蛋白的变化。通过 siRNA 或 shRNA 消除 EGFR 可同时杀死 EGFR 驱动的或 mtKRAS 表达细胞。这表明EGFR蛋白在细胞存活中发挥重要作用，独立其激酶功能。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，我们将研究激酶死亡的 EGFR 是否可以促进细胞生存和拯救 DGD-1202 介导的细胞死亡。在目标 2 中，我们将阐明其机制 DGD-1202 诱导的 EGFR 降解克服了 mtKRAS 介导的 TKI 耐药性。 EGFR蛋白发挥作用重要的支架功能，其消融会导致膜转运蛋白（例如 xCT 和 SGLT1。这些转运蛋白的丢失分别限制了细胞对胱氨酸和葡萄糖的摄取，从而减少了合成谷胱甘肽过氧化物酶，一种关键的自由基清除剂。为了这个目标，我们将研究以下因素的影响： DGD-1202 在 mtKRAS 驱动的癌细胞中诱导 xCT 和 SGLT1 上的 EGFR 降解及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-1202 会降低 wtEGFR 细胞中的 xCT 和 SGLT1 蛋白水平，但对 KD EGFR 表达细胞影响极小，其中 DGD-1202 不会降解 EGFR。最后，在目标 3 中，我们将评估 DGD-1202 在以下方面的功效： mtKRAS 驱动的、EGFR TKI 耐药的异种移植和转基因小鼠模型。我们的初步数据表明 DGD-1202 在几种 mtKRAS 驱动的癌症模型中具有强大的单药活性。为了这个目标，我们将确定剂量和暴露反应曲线。我们还将确定 DGD-1202 的效果长期生存的治疗。该方法将针对广泛的患者并提供治疗对于未经治疗和 EGFR-TKI 耐药的 mtKRAS 驱动的肿瘤都是一种选择。