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

描述(申请人提供)：目前肺癌的治疗包括化疗和放射治疗以及EGFR靶向治疗，已经观察到患者生存的改善。然而，这种疾病最终对这些治疗方法是难治的。因此，发现新的肺癌致癌基因(S)，了解其在肺癌发生中的作用以及对化疗、放射和EGFR-TKI的耐药性，以及开发新的靶向治疗，是一个尚未得到满足的需求。我们已经检测到在一半的非小细胞肺癌(NSCLC)中，丝氨酸/苏氨酸蛋白激酶IKBKE上调和激活。异位表达IKBKE可转化肺上皮细胞AALE-MEK-DD和E10细胞。IKBKE基因的敲除降低了肺癌干细胞和肺癌干细胞，并增强了NSCLC细胞对化疗药物诱导的细胞凋亡的敏感性，而异位表达的IKBKE则表现出相反的作用。我们还鉴定了两种IKBKE的小分子抑制剂。在机制上，我们最近发现IKBKE是通过激活KRAS和EGFR(包括EGFRT790M)突变而激活的，这两个突变导致对EGFR-TKI的原发和获得性耐药。此外，在KRAS和EGFR主要发生突变的NSCLC细胞中，IKBKE基因的敲除选择性地降低了细胞存活率。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突变来确定IKBKE激活的机制和意义；3)检测IKBKE对LCSC和IKBKE的调控，并将其作为克服EGFR-TKI-1和化疗耐药的潜在药物。

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.