Project 2: Identification of combination therapy for KRAS-driven lung cancers.

KRAS是涉及上游酪氨酸的信号通路中的关键调节成分 激酶受体(RTK)，包括EGFR，以及受RAF调控的下游效应通路， 磷脂酰肌醇3-激酶(PI3K)和Ral-GDS。激活KRAS原基因的突变- 癌基因存在于约30%的肺腺癌中，是最常见的 人类癌症的致癌基因突变。尽管EGFR和其他小分子抑制剂 RTK在肺癌患者亚群中显示临床益处，肺癌患者是携带KRAS的肿瘤 事实证明，突变对靶向和化疗方法都是无效的，而且 尽管进行了密集的努力，但还没有有效的疗法来治疗KRAS突变的肺癌。因此， 确定针对肺癌和其他携带KRAS的人类癌症的治疗策略 突变仍然是一个重要的悬而未决的问题，也是一个有实质性临床需求的领域。 在之前的资助期间，我们研究了非规范IB激酶Tbk1作为一种 KRAS驱动的肺癌的靶点。我们阐明了TBK1调节的自分泌回路 促进KRAS驱动的癌症的存活，确定了一种小分子TBK1/JAK抑制剂 在体内抑制KRAS驱动的癌症的生长，启动了一项涉及 该TBK1/JAK抑制剂与临床活性的MEK抑制剂的结合，并鉴定 KRAS定向治疗的耐药机制。 根据观察，致癌的KRAS激活了几个途径和 我们预计，共同推动癌症启动和进展的转录程序 这种联合策略对于开发有效的KRAS治疗方案是必要的- 导致肺癌。我们建议在初步研究的基础上进行身份识别和认证 互补的目标，将允许开发合理的联合疗法 由KRAS引发的肺癌。我们将采用遗传、生化和药理学方法。 为了消除c-raf/mek信号，确定预测和靶向耐药性的方法。 靶向KRAS效应通路和开发联合治疗所调用的机制 建立在MEK和TBK1抑制的基础上。具体地说，我们将使用新技术来产生 基于沙利度胺衍生粘合剂的c-RAF和MEK的靶向降解，我们将 阐明转录调控因子YAP1和YAP1的作用并开发相关的治疗方法 BRD4在抵抗KRAS途径抑制中的作用。这些研究将近距离进行。 与本计划的其他项目和核心进行协作，并将向Rational KRAS驱动的癌症有效联合疗法的发现和发展。

KRAS is a key regulatory component in a signaling pathway that involves upstream tyrosine kinase receptors (RTK), including EGFR, and downstream effector pathways regulated by RAF, phosphatidylinositol 3-kinase (PI3K) and Ral-GDS. Activating mutations of the KRAS proto- oncogene are present in ~30% of lung adenocarcinomas and are among the most common oncogenic mutations in human cancers. Although small molecule inhibitors of EGFR and other RTKs show clinical benefit in subsets of lung cancer patients, tumors that harbor KRAS mutations have proven refractory to both targeted and chemotherapeutic approaches, and despite intensive efforts, no effective therapies exist for KRAS mutated lung cancers. Thus, identifying therapeutic strategies to target lung and other human cancers that harbor KRAS mutations remains an important unsolved problem and an area of substantial clinical need. In the previous funding period, we investigated the non-canonical IB kinase TBK1 as a target in KRAS-driven lung cancers. We elucidated the TBK1-regulated autocrine circuit that promotes the survival of KRAS-driven cancers, identified a small molecule TBK1/JAK inhibitor that inhibited the growth of KRAS-driven cancers in vivo, initiated a clinical trial involving the combination of this TBK1/JAK inhibitor with a clinically active MEK inhibitor, and identified mechanisms of resistance to KRAS-directed therapy. Based on the observation that oncogenic KRAS activates several pathways and transcriptional programs that conspire to drive cancer initiation and progression, we anticipate that combination strategies will be necessary to develop effective treatment regimens for KRAS- driven lung cancers. We propose to build on our preliminary studies to identify and credential complementary targets that will allow the development of rational combination therapies for KRAS-driven lung cancers. We will employ genetic, biochemical and pharmacologic approaches to eliminate c-RAF/MEK signaling, identify approaches to anticipate and target resistance mechanisms invoked by targeting KRAS effector pathways and develop combination therapies building on MEK and TBK1 inhibition. Specifically, we will use new technology to engender targeted degradation of c-RAF and MEK based on thalidomide-derivatized binders, and we will elucidate the role of, and develop therapies related to, the transcriptional regulators YAP1 and BRD4 in resistance to KRAS pathway inhibition. These studies will be performed in close collaboration with the other projects and cores of this Program and will inform the rational identification and development of effective combination therapies for KRAS-driven cancers.