TBK1 Is a Synthetic Lethal Target in Cancer with VHL Loss

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 cereblon-based 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. See related commentary by Bakouny and Barbie, p. 348. This article is highlighted in the In This Issue feature, p. 327

TANK-Binding Kinase 1 (TBK1) Serves as a Potential Target for Hepatocellular Carcinoma by Enhancing Tumor Immune Infiltration

“…Therefore, the up-regulated TBK1 expression, which is predictive of poor prognosis, may contribute to tumor progression especially in BRCA, KIRC, and LIHC. Consistent with our results, other studies reported that ectopic TBK1 expression accelerated the growth of BRCA by phosphorylating estrogen receptor α ( 13 ), and hyperactivated TBK1 was essential for maintaining p62 stability and the oncogenic phenotype of KIRC ( 47 ). However, there is limited knowledge regarding the effect of TBK1 on HCC progression.…”

USP37 promotes deubiquitination of HIF2α in kidney cancer

“…Six-week old female NOD SCID Gamma mice (NSG, Jackson Laboratory) were used for xenograft study. Approximately 5 × 10 5 viable 786-O cells were resuspended in 20 μL fresh growth medium and injected orthotopically into the left kidney of each mouse as described previously (24,25). Bioluminescence imaging was performed as described previously (26).…”

Hypoxia-Driven Effects in Cancer: Characterization, Mechanisms, and Therapeutic Implications

“…Current research has gravitated toward identifying synthetic lethality targets to overcome therapy-resistance and impair cancer growth. We recently identified TBK1 as a synthetic lethal target in VHL-deficient kidney cancer [ 231 ], and inhibitors of TBK1 such as BX795, CYT387 481 (momelotinib), and MRT67307 can boost the efficacy of immune checkpoint inhibitors [ 232 ]. In addition, the use of veliparib, a drug that targets PARP-1, in combination with RAD51 deficiency, resensitizes hypoxic tumor colon carcinoma cells to radiation [ 233 ].…”