Constitutive TBK1 and IKKi Activation Drives Metastatic Prostate Cancer Development
Abstract
Prostate cancer (PCa) is a heterogeneous malignancy that progresses from prostatic intraepithelial neoplasia to locally invasive adenocarcinoma to advanced and metastatic carcinoma. In tumors confined to the prostate, radical prostatectomy and radiotherapy are effective, yet curative treatments are not available for advanced and metastatic PCa. Thus, studies that define novel therapeutic approaches on advanced and metastatic PCa are of great importance. Two enzymes, TBK1 and IKKi, have been recently reported to play important roles in tumor growth and development. In our preliminary studies, we found that both TBK1 and IKKi were highly activated in androgen-independent (AI) PCa cells and that deletion of either IKKi or TBK1 in AI PCa cells had minor effects on cell survival while deletion of both TBK1 and IKKi significantly inhibited cell proliferation and AI PCa growth in mouse models. These results suggest that both TBK1 and IKKi are essential for AI PCa cell survival; inhibiting either one is not enough to inhibit cancer cell proliferation due to the overlap and compensatory function between them. Thus, simultaneously targeting both TBK1 and IKKi is efficient to shut down AI PCa growth. Importantly, mice with deletion of IKKi are viable and largely normal. Deletion of TBK1 induces tumor cell death, while non-tumorigenic epithelial cells do not depend on TBK1 for survival. Thus, targeting both TBK1 and IKKi will not be only an effective means of blocking tumor growth but also a safe way that would yield few side effects. Therefore, TBK1 and IKKi are ideal targets for the treatment of AI and metastatic PCa. In this proposed study, we will define the role of TBK1 and IKKi in the development of AI and metastatic PCa. We will define how TBK1/IKKi are constantly activated and how activated TBK1/IKKi promote AI and metastatic PCa growth. We will also examine the relevance of TBK1/IKKi activation to human prostate cancer progression, metastasis, and therapy resistance. Our studies will lay the foundation for developing novel therapeutic strategies for the treatment and/or prevention of AI and metastatic PCa. Importantly, we have developed a series of potent TBK1/IKKi dual inhibitors with drug-like properties in PI s lab. Therefore, once our proposed study demonstrates that TBK1/IKKi are important targets for the treatment of AI and metastatic PCa, our novel TBK1/IKKi dual inhibitors will be used in preclinical and clinical test for the treatment of this lethal disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510235
Entities
People
- Jun-Li Luo
Organizations
- Scripps Research
- United States Army