Identification of TBK1 inhibitors in KRAS-dependent lung cancer

KRAS 依赖性肺癌中 TBK1 抑制剂的鉴定

• 批准号: 8237125
• 负责人: William C. Hahn
• 金额: $ 42.96万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-11 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8237125
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adverse effects; Alleles; Animal Model; Antibodies; Area; BRCA1 gene; Binding; Biochemical; Biochemical Genetics; Biological; Biological Process; Biology; Cancer Patient; Cancer cell line; Cell Death; Cell Line; Cell model; Cells; Chemicals; Chemistry; Clinical; Collaborations; Consensus; Development; ERBB2 gene; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Foundations; Genes; Genetic; Goals; Human; In Vitro; Instruction; Investigation; KRAS2 gene; Lead; Lung; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Mammalian Cell; Mediating; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncogenic; PARP inhibition; Pathway interactions; Phenotype; Phospho-Specific Antibodies; Phosphotransferases; Property; Protein Kinase; Protein-Serine-Threonine Kinases; Proteins; Proteomics; Proto-Oncogenes; RNA Interference; Receptor Protein-Tyrosine Kinases; Refractory; Research Personnel; Role; Screening procedure; Signal Pathway; Signal Transduction; Site; Structure; Technology; Testing; Therapeutic; Therapeutic Agents; Work; base; chemotherapy; clinically significant; cytotoxic; drug development; functional genomics; in vivo; inhibitor/antagonist; insight; malignant breast neoplasm; mutant; novel therapeutics; programs; small molecule; theories; therapeutic target; translational study; tumor

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.

项目摘要（请参阅说明）： KRAS是信号通路中的关键调节成分，涉及上游酪氨酸激酶受体和下游效应途径，该效应途径由磷脂酰肌醇3-激酶（PI3K）和RAF调节。 -30％的肺腺癌中存在KRAS原癌基因的激活突变，并且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均显示出肺癌患者亚群的临床益处，但携带KRAS突变的肿瘤已证明对治疗难治性，并且KRAS的分子抑制剂尚不存在。因此，确定靶向肺癌和携带KRAS突变的其他人类癌症的治疗策略仍然是一个重要的未解决问题和巨大的临床需求领域。 在最近的工作中，我们使用了系统的功能基因组方法来识别丝氨酸苏氨酸激酶TBK1作为一种基因，其表达对于KRAS驱动的非小细胞肺癌（NSCLC）细胞系的存活至关重要。 TBK1激活NF-KB途径，并在体外和体内促进KRAS依赖性细胞系的存活。这些新的观察结果不仅确定了对KRAS驱动癌症生存至关重要的潜在可吸毒靶标，而且还暗示了NF-KB途径是依赖KRAS的肺癌子集的靶标。 基于这些观察结果，该提案着重于测试NSCLC中的新型可操作的治疗靶标。1特别是，将使用生物化学，遗传和化学生物学方法（1）使用（1）来识别TBK1底物所必需的TBK1底物，以识别kras依赖性tumore的生存3（2），并依赖于kras依赖性tumorec（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）。研究NF-KB途径在KRAS依赖性NSCLC中的作用。这些研究将与该计划的其他项目和核心密切合作进行。这些研究不仅将增强我们对这种非规范IKK调节剂的机械理解，而且还将确定化合物，这些化合物将构成以治疗靶向这种激酶的策略的基础。