TBK1 is a synthetic lethal target in cancer with VHL loss

Lianxin Hu, Haibiao Xie, Xijuan Liu, Frances Potjewyd, Lindsey I. James, Emily M. Wilkerson, Laura E. Herring, Ling Xie, Xian Chen, Johnny Castillo Cabrera, Kai Hong, Chengheng Liao, Xianming Tan, Albert S. Baldwin, Kan Gong, Qing Zhang

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

TANK binding kinase 1 (TBK1) is an important kinase involved in the innate immune response. Here we discover that TBK1 is hyperactivated by von Hippel-Lindau (VHL) loss or hypoxia in cancer cells. Tumors from patients with kidney cancer with VHL loss display elevated TBK1 phosphorylation. Loss of TBK1 via genetic ablation, pharmacologic inhibition, or a new cereblonbased proteolysis targeting chimera specifically inhibits VHL-deficient kidney cancer cell growth, while leaving VHL wild-type cells intact. TBK1 depletion also significantly blunts kidney tumorigenesis in an orthotopic xenograft model in vivo. Mechanistically, TBK1 hydroxylation on Proline 48 triggers VHL as well as the phosphatase PPM1B binding that leads to decreased TBK1 phosphorylation. We identify that TBK1 phosphorylates p62/SQSTM1 on Ser366, which is essential for p62 stability and kidney cancer cell proliferation. Our results establish that TBK1, distinct from its role in innate immune signaling, is a synthetic lethal target in cancer with VHL loss. SIGNIFICANCE: The mechanisms that lead to TBK1 activation in cancer and whether this activation is connected to its role in innate immunity remain unclear. Here, we discover that TBK1, distinct from its role in innate immunity, is activated by VHL loss or hypoxia in cancer.

Original languageEnglish (US)
Pages (from-to)460-475
Number of pages16
JournalCancer discovery
Volume10
Issue number3
DOIs
StatePublished - Mar 2020

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Hu, L., Xie, H., Liu, X., Potjewyd, F., James, L. I., Wilkerson, E. M., Herring, L. E., Xie, L., Chen, X., Cabrera, J. C., Hong, K., Liao, C., Tan, X., Baldwin, A. S., Gong, K., & Zhang, Q. (2020). TBK1 is a synthetic lethal target in cancer with VHL loss. Cancer discovery, 10(3), 460-475. https://doi.org/10.1158/2159-8290.CD-19-0837