Co-targeting S6 and TAM kinases in PTEN-deficient glioblastoma

共靶向S6和蛋白激酶在PTEN缺陷性胶质母细胞瘤中的作用 项目摘要 核糖体S6蛋白激酶(S6Ks)在肿瘤抑制基因PTEN缺失后被激活 胶质母细胞瘤和其他实体和造血组织的癌症。我们之前曾报道过基因 S6K1的失活抵消了肿瘤中PTEN缺失的代谢和抗凋亡作用，这是一致的 在可比较的环境中进行了几次观察。最近，我们研究了药物抑制剂， 靶向S6K1，这导致了PTEN特异性的对S6K1的组合抑制的脆弱性 以及家族的酪氨酸激酶。酪氨酸家族是以其成员命名的，该家族 是Tyro3、AXL和MERTK。酪氨酸激酶在肿瘤学中具有很高的靶向性，因为有几种 对这三种药物都有活性的晚期临床试验和FDA批准的酪氨酸激酶抑制剂 会员。在验证阶段，使用遗传方法研究PTEN选择性的要求 细胞毒性，结果表明，激酶的失活足以使PTEN缺陷的细胞对 S6K1的抑制作用。在目前的研究应用中，我们建议扩大S6和S6的遗传分析 解释了与PTEN缺陷性胶质母细胞瘤发生相关的蛋白激酶的机制。 实验将利用CRISPR Cas9基因组编辑技术来灭活S6K和 激酶家族成员，单独或组合，同时决定信号和代谢的影响。型号 系统将使用患者来源的肿瘤样本来评估遗传结果的普遍性和适用性 胶质母细胞瘤肿瘤/细胞的生理功能。我们预计，结果将提供 机制框架，将为制定影响S6K的有针对性的治疗策略提供信息 以及TAMs本身，或作为其路径一部分的信号组件。

Co-targeting S6 and TAM kinases in PTEN-deficient glioblastoma Project Summary The ribosomal S6 protein kinases (S6Ks) are activated in response to loss of the tumor suppressor PTEN in glioblastoma and other cancers of solid and hematopoietic tissues. We previously reported that genetic inactivation of S6K1 counteracts the metabolic and anti-apoptotic effects of PTEN loss in cancer, in agreement with several observations in comparable settings. Recently we investigated pharmacological inhibitors that target S6K1, which led to the identification of a PTEN-specific vulnerability to combination inhibition of S6K1 together with the TAM family of tyrosine kinases. The TAM family of tyrosine is named for its members, which are TYRO3, AXL, and MERTK. TAM tyrosine kinases are highly targetable in oncology, as there are several late-stage clinical trial and FDA-approved tyrosine kinase inhibitors that have activity against all three members. In a validation phase using genetic approaches to investigate the requirements for PTEN-selective cytotoxicity, results revealed that inactivation of TAM kinases is sufficient to sensitize PTEN-deficient cells to inhibition of S6K1. In the present research application, we propose to extend the genetic analysis of S6 and TAM kinases to elucidate the mechanisms that relate the kinases in the setting of PTEN-deficient glioblastoma. Experiments will make use of CRISPR Cas9 genome editing technologies to inactivate the S6K and TAM kinase family members, alone or in combination, while determining signaling and metabolic effects. Model systems will employ patient-derived tumor samples to assess the generality and applicability of genetic results to physiologic functions of glioblastoma tumors/cells. We anticipate that the results will provide the mechanistic framework that will inform the development of targeted therapeutic strategies affecting the S6Ks and TAMs themselves, or signaling components that are part of their pathways.