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疗以及EGFR靶向治疗，已观察到患者生存的改善。然而，这种疾病最终对这些治疗是难治的。因此，发现新的肺癌致病基因，了解其在肺癌发生中的作用以及放化疗和egfr - tki耐药，并开发新的靶向治疗方法是一个未满足的需求。我们已经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异位表达转化肺上皮AALE-MEK-DD和E10细胞。IKBKE的下调可降低肺癌干细胞、LCSC，并使非小细胞肺癌细胞对化疗药物诱导的凋亡敏感，而IKBKE的异位表达则表现出相反的作用。我们还鉴定出2种IKBKE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了KRAS和EGFR主要突变的NSCLC细胞的细胞存活率。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突变确定IKBKE激活的机制和意义；3)研究IKBKE调控LCSC和IKBKE作为靶点及其抑制剂作为克服EGFR- tki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.