Purpose: Protein kinases are known to play a prominent role in oncogenic progression across multiple cancer subtypes, yet their role in prostate cancer progression remains underexplored. The purpose of this study was to identify kinases that drive prostate cancer progression. Experimental Design: To discover kinases that drive prostate cancer progression, we investigated the association between gene expression of all known kinases and longterm clinical outcomes in tumor samples from 545 patients with high-risk disease. We evaluated the impact of genetic and pharmacologic inhibition of the most significant kinase associated with metastatic progression in vitro and in vivo. Results: DNA-dependent protein kinase (DNAPK) was identified as the most significant kinase associated with metastatic progression in high-risk prostate cancer. Inhibition of DNAPK suppressed the growth of both AR-dependent and AR-independent prostate cancer cells. Gene set enrichment analysis nominated Wnt as the top pathway associated with DNAPK. We found that DNAPK interacts with the Wnt transcription factor LEF1 and is critical for LEF1-mediated transcription. Conclusions: Our data show that DNAPK drives prostate cancer progression through transcriptional regulation ofWnt signaling and is an attractive therapeutic target in aggressive prostate cancer.
Bibliographical noteFunding Information:
This work was supported by a grant to V. Kothari and S.G. Zhao from the PCF, to F.Y. Feng, K.E. Knudsen and S.A. Tomlins from the PCF/Evans Foundation, K.E. Knudsen from PA CURE and NCI (CA159945, CA176401), F.Y. Feng and V. Kothari from the DOD PCa Idea Development Award No. W81XWH1810599
© 2019 American Association for Cancer Research.