IKBKE/IKKE (epsilon) Kinase in Non-small Cell Lung Cancer

非小细胞肺癌中的 IKBKE/IKKE (epsilon) 激酶

• 批准号: 8388171
• 负责人: Jin Q Cheng
• 金额: $ 34.96万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8388171
• 关键词: Accounting; Alveolar; Apoptosis; Binding; Biology; Breast; Cancer Etiology; Cancer cell line; Cell Death; Cell Survival; Cells; Cessation of life; Characteristics; Chinese Traditional Medicine; Clara cell-specific protein; Clinic; Clinical Trials; Collection; Development; Diagnosis; Disease; Doxycycline; Ectopic Expression; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epithelial; Exhibits; Family; Family member; Foundations; Genes; Human; Investigation; KRAS2 gene; Libraries; Lung; Lung Adenoma; MEKs; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mediating; Molecular; Mus; Mutate; Mutation; Names; Nature; Non-Small-Cell Lung Carcinoma; Oncogenes; PDPK1 gene; PH Domain; Patients; Pharmaceutical Preparations; Phosphotransferases; Play; Population; Protein-Serine-Threonine Kinases; Proto-Oncogene Protein c-kit; Proto-Oncogene Proteins c-akt; Radiation; Refractory; Regulation; Reporting; Resistance; Role; Screening procedure; Staging; TBK1 gene; United States; Up-Regulation; Xenograft Model; aldehyde dehydrogenases; base; cancer cell; cancer stem cell; cancer therapy; chemotherapy; feeding; improved; inhibitor/antagonist; insight; loss of function; lung carcinogenesis; lung tumorigenesis; member; mutant; novel; novel therapeutics; promoter; small molecule; stem cell division; therapeutic target; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Current treatment of lung cancer includes chemotherapy and radiation as well as EGFR- targeted therapy, the improvement for patient survival has been observed. However, the disease is eventually refractory to these treatments. Thus, there is an unmet need to identify new lung cancer causing gene(s), understand its role in lung carcinogenesis and the chemoradio- and EGFR-TKI-resistance and to develop new targeted therapy. We have detected upregulation and activation of IKBKE, a serine/threonine protein kinase, in a half of non-small cell lung cancers (NSCLC). Ectopic expression of IKBKE transforms lung epithelial AALE-MEK-DD and E10 cells. Knockdown of IKBKE decreases lung cancer stem cell, LCSC, and sensitizes NSCLC cells to chemotherapeutic drug-induced apoptosis, whereas ectopic expression of IKBKE exhibits opposite effects. We have also identified 2 small molecule inhibitors of IKBKE. Mechanistically, we have recently found that IKBKE is activated by activating mutations of KRAS and EGFR (including EGFRT790M) which cause primary and acquired resistance to EGFR-TKI. Furthermore, knockdown of IKBKE selectively reduces cell survival in NSCLC cells in which KRAS and EGFR are dominantly mutated. Based on these findings, we are going to 1) determine the role of gain and loss of function of IKBKE in lung tumorigenesis; 2) ascertain the mechanism and the significance of IKBKE activation by activating mutations of EGFR and KRAS and 3) examine IKBKE regulation of LCSC and IKBKE as a target and its inhibitors as potential agents to overcome EGFR-TKI- and chemo- resistance. PUBLIC HEALTH RELEVANCE: In order to improve lung cancer treatment, novel targeted therapy is urgently needed. Our study points out that IKBKE could play a pivotal role in lung carcinogenesis and that IKBKE is activated by KRAS and EGFR and could serve as a critical target for overcoming EGFR-TKI resistance and for intervening lung cancer. Therefore, further investigation of the role and mechanism of IKBKE in lung oncogenesis and IKBKE inhibitors in EGFR-TKI- and chemo-resistance will not only provide insight into the biology of the IKBKE in lung cancer but will lay a foundation for the development of novel therapeutics.

描述（由申请人提供）：目前肺癌的治疗包括化疗和放疗以及EGFR靶向治疗，已观察到患者生存期的改善。然而，这种疾病最终对这些治疗是难治的。因此，对于鉴定新的肺癌致病基因、了解其在肺癌发生中的作用以及放化疗和EGFR-TKI抗性以及开发新的靶向疗法存在未满足的需求。我们在一半的非小细胞肺癌（NSCLC）中检测到IKBKE（一种丝氨酸/苏氨酸蛋白激酶）的上调和激活。IKBKE的异位表达转化肺上皮AALE-MEK-DD和E10细胞。IKBKE的敲低减少肺癌干细胞，LCSC，并敏感的NSCLC细胞化疗药物诱导的凋亡，而异位表达的IKBKE表现出相反的效果。我们还鉴定了IKBKE的2种小分子抑制剂。从机制上讲，我们最近发现IKBKE是通过激活KRAS和EGFR（包括EGFRT 790 M）的突变而激活的，这些突变导致对EGFR-TKI的原发性和获得性耐药。此外，IKBKE的敲低选择性地降低其中KRAS和EGFR显性突变的NSCLC细胞中的细胞存活。基于这些发现，我们将1）确定IKBKE功能的获得和丧失在肺肿瘤发生中的作用; 2）通过激活EGFR和KRAS的突变来确定IKBKE激活的机制和意义; 3）检查LCSC的IKBKE调节和IKBKE作为靶标及其抑制剂作为克服EGFR-TKI和化疗耐药性的潜在药物。 公共卫生相关性：为了改善肺癌治疗，迫切需要新的靶向治疗。我们的研究指出，IKBKE可能在肺癌发生中发挥关键作用，并且IKBKE被KRAS和EGFR激活，可以作为克服EGFR-TKI耐药性和干预肺癌的关键靶点。因此，进一步研究IKBKE在肺癌发生中的作用和机制以及IKBKE抑制剂在EGFR-TKI-和化疗耐药中的作用，不仅可以深入了解IKBKE在肺癌中的生物学作用，而且将为开发新的治疗方法奠定基础。