Identification of TBK1 inhibitors in KRAS-dependent lung cancer

项目总结(见说明)： KRAS是受磷脂酰肌醇3-激酶(PI3K)和RAF调节的上游酪氨酸激酶受体和下游效应通路中的关键调节成分。KRAS原癌基因的激活突变存在于-30%的肺腺癌中，是人类癌症中最常见的致癌突变之一。尽管EGFR和PI3K的抗体和小分子抑制剂在肺癌患者的亚群中都显示出临床益处，但携带KRAS突变的肿瘤已被证明对治疗无效，目前还不存在KRAS的小分子抑制剂。因此，确定针对肺癌和其他携带KRAS突变的人类癌症的治疗策略仍然是一个重要的尚未解决的问题，也是一个具有巨大临床需求的领域。 在最近的工作中，我们使用系统的功能基因组方法来确定丝氨酸苏氨酸激酶TBK1是一个对KRAS驱动的非小细胞肺癌(NSCLC)细胞系的生存至关重要的基因。在体外和体内，TBK1激活了核因子-KB途径，促进了KRAS依赖细胞系的存活。这些新的观察结果不仅确定了一个对KRAS驱动的癌症的生存至关重要的潜在的可药物靶点，而且还暗示了NF-KB通路是依赖KRAS的肺癌亚群的靶点。 在此基础上，本研究的重点是检测TBK1和NF-KB通路是否为NSCLC新的治疗靶点。1具体而言，将使用生化、遗传和化学生物学方法(1)确定KRAS依赖型肿瘤生存所需的TBK1底物，(2)开发TBK1的小分子抑制剂，以及(3)研究NF-KB通路在KRAS依赖型NSCLC中的作用。这些研究将与本方案的其他项目和核心密切合作进行。这些研究不仅将加强我们对这种非规范的IKK调节因子的机制的理解，而且还将识别形成针对该激酶的治疗策略的基础的化合物。

PROJECT SUMMARY (See instructions): KRAS serves as a key regulatory component in a signaling pathway that involves both upstream tyrosine kinase receptors and downstream effector pathways regulated by phosphatidylinositol 3-kinase (PI3K) and RAF. Activating mutations of the KRAS proto-oncogene are present in -30% lung adenocarcinomas and are among the most common oncogenic mutations in human cancers. Although both antibody and small molecule inhibitors of EGFR and PI3K show clinical benefit in subsets of lung cancer patients, tumors that harbor KRAS mutations have proven refractory to treatment, and no small molecule inhibitors of KRAS yet exist. Thus, identifying therapeutic strategies to target lung and other human cancers that harbor KRAS mutations remains an important unsolved problem and an area of tremendous clinical need. In recent work, we have used systematic functional genomic approaches to identify the serine threonine kinase TBK1 as a gene whose expression is essential for the survival of KRAS-driven non-small cell lung cancer (NSCLC) cell lines. TBK1 activates the NF-KB pathway and promotes the survival of KRAS dependent cell lines both in vitro and in vivo. These new observations not only identify a potentially druggable target that is essential for the survival of KRAS-driven cancers but also implicate the NF-KB pathway as a target for the subset of lung cancers that are dependent on KRAS. Based on these observations, this proposal focuses on testing whether TBKl and the NF-KB pathway are new actionable therapeutic targets in NSCLC.1Specifically, biochemical, genetic, and chemical biological approaches will be used (1) to identify TBK1 substrates necessary for the survival of KRAS-dependent tumors, (2) to develop small molecule inhibitors of TBK1, and (3) to investigate the role of NF-KB pathway in KRAS-dependent NSCLC. These studies will be performed in close collaboration with the other projects and cores of this Program. These studies will not only enhance our mechanistic understanding of this noncanonical IKK regulator but will also identify chemical compounds that will form the foundation for strategies to target this kinase therapeutically.