TBK1 is a Synthetic Lethal Target in Cancer with VHL Loss

TANK Binding Kinase 1 (TBK1) is an important kinase involved in innate immune response. Here we discover that TBK1 is hyperactivated by von Hippel-Lindau (VHL) loss or hypoxia in cancer cells. Tumors from kidney cancer patients with VHL loss display elevated TBK1 phosphorylation. Loss of TBK1 via genetic ablation, pharmacological inhibition, or a new Cereblon-based proteolysis targeting chimera (PROTAC) 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, distinctive from its role in innate immune signaling, is a synthetic lethal target in cancer with VHL loss.