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

Summary

Principal Investigator: Jin Q Cheng
Abstract: 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.
Funding Period: 2012-09-01 - 2017-06-30
more information: NIH RePORT

Top Publications

  1. pmc PHF20 is an effector protein of p53 double lysine methylation that stabilizes and activates p53
    Gaofeng Cui
    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA
    Nat Struct Mol Biol 19:916-24. 2012
  2. pmc MicroRNA miR-214 regulates ovarian cancer cell stemness by targeting p53/Nanog
    Cheng Xiong Xu
    Department of Molecular Oncology, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
    J Biol Chem 287:34970-8. 2012
  3. pmc Upregulation of miRNA-155 promotes tumour angiogenesis by targeting VHL and is associated with poor prognosis and triple-negative breast cancer
    W Kong
    Department of Molecular Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
    Oncogene 33:679-89. 2014
  4. pmc IKBKE phosphorylation and inhibition of FOXO3a: a mechanism of IKBKE oncogenic function
    Jian Ping Guo
    Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing, China
    PLoS ONE 8:e63636. 2013
  5. ncbi Aurora-A is a determinant of tamoxifen sensitivity through phosphorylation of ERα in breast cancer
    X Q Zheng
    1 Department of Molecular Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA 2 Departments of Thyroid and Neck Tumour, Tianjin Medical University Cancer Institute and Hospital, Oncology Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin, PR China 3 Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Oncology Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin, PR China
    Oncogene 33:4985-96. 2014

Detail Information

Publications5

  1. pmc PHF20 is an effector protein of p53 double lysine methylation that stabilizes and activates p53
    Gaofeng Cui
    Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA
    Nat Struct Mol Biol 19:916-24. 2012
    ..Overall our work establishes that PHF20 functions as an effector of p53 methylation that stabilizes and activates p53...
  2. pmc MicroRNA miR-214 regulates ovarian cancer cell stemness by targeting p53/Nanog
    Cheng Xiong Xu
    Department of Molecular Oncology, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
    J Biol Chem 287:34970-8. 2012
    ..Expression of p53 abrogated miR-214-induced OCSC properties. These data suggest the critical role of miR-214 in OCSC via regulation of the p53-Nanog axis and miR-214 as a therapeutic target for ovarian cancer...
  3. pmc Upregulation of miRNA-155 promotes tumour angiogenesis by targeting VHL and is associated with poor prognosis and triple-negative breast cancer
    W Kong
    Department of Molecular Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
    Oncogene 33:679-89. 2014
    ....
  4. pmc IKBKE phosphorylation and inhibition of FOXO3a: a mechanism of IKBKE oncogenic function
    Jian Ping Guo
    Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing, China
    PLoS ONE 8:e63636. 2013
    ..These findings suggest that IKBKE regulates FOXO3a primarily through phosphorylation of SerS644 and that IKBKE exerts its cellular function, at least to some extent, through regulation of FOXO3a...
  5. ncbi Aurora-A is a determinant of tamoxifen sensitivity through phosphorylation of ERα in breast cancer
    X Q Zheng
    1 Department of Molecular Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA 2 Departments of Thyroid and Neck Tumour, Tianjin Medical University Cancer Institute and Hospital, Oncology Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin, PR China 3 Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Oncology Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin, PR China
    Oncogene 33:4985-96. 2014
    ....

Research Grants30

  1. Protein Kinase Therapeutic Targets for Non-Small Cell Lung Carcinoma
    Matthew L Meyerson; Fiscal Year: 2013
    ..Our insight into resistance to EGFR inhibitors will be used to design new inhibitors that overcome drug resistance mutations for all three targets. ..
  2. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
    ....
  3. Chemopreventive effect of fish oil derived EPA in lung cancer
    Peiying Yang; Fiscal Year: 2013
    ..This proposal intends to define a novel targeted natural chemopreventive agent against lung cancer. ..
  4. Interrogating Epigenetic Changes in Cancer Genomes
    Tim H M Huang; Fiscal Year: 2013
    ..abstract_text> ..
  5. Characterization of Pathways Controlling Cancer at the Level of Gene Regulation
    Phillip A Sharp; Fiscal Year: 2013
    ..The interactions and involvement of Rb and miRNAs in induction of cell death following DNA damage will also be studied. ..