Development of a first-in-class mEGFR dimerization inhibitor

开发一流的 mEGFR 二聚化抑制剂

• 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
• 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

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.

项目总结/摘要 KRAS突变（mtKRAS）发生在大约25%的人类肿瘤中，并赋予对肿瘤的耐药性。 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 开发DGD-1202，一种活化EGFR激酶的特异性降解剂，而不是抑制剂， 对mtKRAS驱动的鼠肿瘤模型的活性。我们的数据表明， 而不影响mtKRAS水平可能是TKI耐药mtKRAS驱动的肿瘤的新疗法。我们 假设在这种wtEGFR/mtKRAS肿瘤类型中，EGFR激酶非依赖性作用对于细胞 生存因此，活化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的疗效和作用机制。因此 这项建议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 EGFR蛋白在mtKRAS驱动的肿瘤中的作用。通过siRNA或shRNA切除EGFR可以杀死EGFR驱动的细胞 或表达mtKRAS的细胞。这表明EGFR蛋白在细胞存活中起重要作用，独立于 它的激酶功能。我们假设激酶死亡（KD）EGFR蛋白表达将挽救细胞死亡 在这些细胞中由EGFR消融诱导。在这个目标中，我们将研究激酶死亡的EGFR是否可以促进细胞增殖， 存活和拯救DGD-1202介导的细胞死亡。在目标2中，我们将阐明 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，其消融导致膜转运蛋白如xCT和 SGLT 1.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，从而降低了细胞对胱氨酸和葡萄糖的摄取。 关键自由基清除剂谷胱甘肽过氧化物酶的合成。为此，我们将研究 DGD-1202诱导mtKRAS驱动的癌细胞中xCT和SGLT 1上的EGFR降解及其对细胞增殖的影响 活性氧中间体的积累。根据我们的初步数据，我们假设DGD-1202 将降低wtEGFR细胞中的xCT和SGLT 1蛋白水平，但对KD EGFR表达细胞的影响极小， 其中DGD-1202不降解EGFR。最后，在目标3中，我们将评估DGD-1202在以下患者中的疗效： 一组mtKRAS驱动的EGFR TKI抗性异种移植物和转基因小鼠模型。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稳健的单一药剂活性。在这一目标下， 我们将确定剂量和剂量反应曲线。我们还将确定DGD-1202的效果 长期生存的治疗。这种方法将针对广泛的患者， 对于未经治疗的和EGFR-TKI耐药的mtKRAS驱动的肿瘤都是一种选择。