ABL kinases promote lung cancer brain metastasis through regulation of transcriptional networks

ABL激酶通过调控转录网络促进肺癌脑转移

• 批准号: 10064468
• 负责人: Benjamin Jacob Mayro
• 金额: $ 3.75万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064468
• 关键词: ABL1 gene; ABL2 gene; Accounting; Binding Sites; Biological Markers; Blood - brain barrier anatomy; Brain; Cancer Etiology; Cancer Patient; Cancer cell line; Cell Hypoxia; Cells; Cessation of life; Chromatin; Clinical; Cranial Irradiation; Data; Diagnosis; Drug resistance; Epidermal Growth Factor Receptor; Exhibits; Family; Genes; Genetic; Genetic Transcription; High Prevalence; Hypoxia; Hypoxia Inducible Factor; Impaired cognition; Impairment; Laboratories; Link; Luciferases; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Messenger RNA; Metastatic malignant neoplasm to brain; Modeling; Molecular; Mutation; Neoplasm Metastasis; Oncogenic; Outcome; Pathway interactions; Patients; Pharmacology; Phosphotransferases; Protein Tyrosine Kinase; Proteins; Radiation therapy; Resistance; Risk; Role; Signal Transduction; Solid Neoplasm; Survival Rate; Time; Transcription Coactivator; Transcriptional Activation; Transcriptional Regulation; Tropism; Up-Regulation; axl receptor tyrosine kinase; base; blood-brain barrier permeabilization; cancer cell; cancer type; chemotherapy; comparative; driver mutation; drug development; genetic signature; in vitro Assay; in vivo; in vivo Model; inhibitor/antagonist; insight; kinase inhibitor; knock-down; loss of function; mortality; mouse model; mutant; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; outcome forecast; overexpression; patient biomarkers; patient subsets; programs; response; targeted treatment; therapy resistant; transcription factor; transcriptome; treatment strategy; tumor; upstream kinase

ABSTRACT Lung cancer has the highest prevalence of brain metastasis among all other cancer types, occurring in approximately 40% of patients. The presence of lung cancer brain metastases (LCBM) is associated with cognitive decline and a median survival of 4-6 months. Currently utilized therapies for treating LCBMs include whole brain radiation therapy (WBRT), chemotherapies, and targeted therapies aimed at kinases with “driver” mutations. The use of WBRT increases patient cognitive decline, while targeted therapies have been proven ineffective due to variable responses and the development of drug resistance. Thus, there is an obvious unmet clinical need to better understand the molecular mechanisms that promote LCBM and subsequently use these discoveries to develop new therapeutic strategies. Our laboratory discovered using an in vivo model of brain metastasis that Abelson tyrosine protein kinase 2 (ABL2) promotes LCBM by propagating a feed-forward loop consisting of ABL2, AXL receptor tyrosine kinase, and the TAZ transcriptional co-activator. Recently, my preliminary data revealed an ABL-dependent stabilization and transcriptional activation of hypoxia inducible factor-1α (HIF-1α) and heatshock factor 1 (HSF1) in this model. Activation of the HIF-1α and HSF1 transcription networks in cancer is associated with tumor proliferation, metastasis, and therapy resistance. Therefore, my central hypothesis is that the ABL kinases regulate multiple transcriptional networks that promote lung cancer brain metastasis and therapy resistance. I will examine this hypothesis through the following two aims: 1) Define the ABL-regulated HIF-1α transcription network required for lung cancer brain metastasis, and 2) Identify ABL- dependent HSF1- regulated pathways necessary for lung cancer colonization of the brain. These aims will evaluate whether increased expression of HIF-1α, HSF1, and TAZ can be used as biomarkers for lung cancer patients with brain metastasis and whether blood brain barrier permeable ABL kinase inhibitors might be an effective novel therapy for treating brain metastatic lung cancer.

抽象的 在所有其他癌症类型中，肺癌的脑转移发生率最高，发生在 大约 40% 的患者存在肺癌脑转移 (LCBM)。 目前用于治疗 LCBM 的疗法包括认知能力下降和中位生存期为 4-6 个月。 全脑放射治疗（WBRT）、化疗和针对具有“驱动器”的激酶的靶向治疗 WBRT 的使用会增加患者认知能力的下降，而靶向治疗已被证明。 由于不同的反应和耐药性的发展而无效，因此，存在明显的未满足的问题。 临床需要更好地了解促进 LCBM 的分子机制并随后使用这些机制 我们的实验室发现使用大脑的体内模型来开发新的治疗策略。 Abelson 酪氨酸蛋白激酶 2 (ABL2) 通过传播前馈循环促进 LCBM 转移 由 ABL2、AXL 受体酪氨酸激酶和 TAZ 转录共激活因子组成。 初步数据揭示了缺氧诱导的 ABL 依赖性稳定和转录激活 该模型中的因子 1α (HIF-1α) 和热休克因子 1 (HSF1) HIF-1α 和 HSF1 转录的激活。 癌症网络与肿瘤增殖、转移和治疗耐药性相关。 中心假设是 ABL 激酶调节促进肺癌的多个转录网络 我将通过以下两个目标来检验这一假设：1）定义。 肺癌脑转移所需的 ABL 调节的 HIF-1α 转录网络，以及 2) 识别 ABL- 依赖HSF1调节肺癌在大脑中定植的必要途径。 评估 HIF-1α、HSF1 和 TAZ 表达的增加是否可以用作肺癌的生物标志物 脑转移患者以及血脑屏障可渗透的 ABL 激酶抑制剂是否可能是一种治疗方法 治疗脑转移性肺癌的有效新疗法。