TBK1 Is a Synthetic Lethal Target in Cancer with VHL Loss

被引：96

作者：

Hu, Lianxin ^{[1
,2
]}

Xie, Haibiao ^{[3
]}

Liu, Xijuan ^{[1
]}

Potjewyd, Frances ^{[4
]}

James, Lindsey, I ^{[4
]}

Wilkerson, Emily M. ^{[5
]}

Herring, Laura E. ^{[5
]}

Xie, Ling ^{[6
]}

Chen, Xian ^{[6
]}

Cabrera, Johnny Castillo ^{[1
]}

Hong, Kai ^{[7
]}

Liao, Chengheng ^{[1
,2
]}

Tan, Xianming ^{[1
]}

Baldwin, Albert S. ^{[1
]}

Gong, Kan ^{[3
]}

Zhang, Qing ^{[1
,2
,5
,8
]}

机构：

[1] Univ N Carolina, Lineberger Comprehens Canc Ctr, Sch Med, Chapel Hill, NC 27515 USA

[2] Univ Texas Southwestern Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA

[3] Peking Univ, Dept Urol, Hosp 1, 8 Xishiku St, Beijing 100034, Peoples R China

[4] Univ N Carolina, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27515 USA

[5] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27515 USA

[6] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27515 USA

[7] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Med Ultrasound, Wuhan, Hubei, Peoples R China

[8] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27515 USA

来源：

CANCER DISCOVERY | 2020年 / 10卷 / 03期

关键词：

RENAL-CELL CARCINOMA; B KINASE EPSILON; PROLINE HYDROXYLATION; HIF-ALPHA; AUTOPHAGY; OXYGEN; INHIBITION; REVEALS; TUMORIGENESIS; BLOCKADE;

D O I：

10.1158/2159-8290.CD-19-0837

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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.

引用

页码：460 / 475

页数：16

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