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

摘要 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。肺癌脑转移(LCBM)的存在与 认知能力下降，中位生存期为4-6个月。目前用于治疗LCBM的疗法包括 全脑放射治疗(WBRT)、化疗和靶向治疗 突变。WBRT的使用增加了患者认知能力的下降，而靶向治疗已被证明 由于反应多变和产生抗药性而无效。因此，有一个明显的未得到满足的 临床需要更好地了解促进LCBM的分子机制，并随后使用这些 开发新的治疗策略的发现。我们实验室利用活体大脑模型发现了 Abelson酪氨酸蛋白激酶2(ABL2)通过传播前馈环路促进LCBM的转移 由ABL2、Ax1受体酪氨酸激酶和TAZ转录共激活因子组成。最近，我的 初步数据显示低氧诱导的ABL依赖的稳定和转录激活 该模型中的因子-1α(HIF-1α)和热休克因子1(HSF1)。缺氧诱导因子-1α和热休克因子1转录的激活 肿瘤中的网络与肿瘤的增殖、转移和治疗耐药有关。因此，我的 中心假说是ABL激酶调节促进肺癌的多个转录网络 脑转移与治疗抵抗。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；2)鉴定abl-1 肺癌脑内定植所必需的依赖HSF1调节的通路。这些目标将 评价HIF-1α、HSF-1和TAZ的高表达是否可作为肺癌的生物标志物 脑转移患者和血脑屏障通透性ABL激酶抑制剂是否可能是一种 治疗脑转移肺癌的有效新疗法。

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.