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Enzyme Identified as Potential Target in von Hippel-Lindau–Deficient Kidney Cancer

By: Sarah Campen, PharmD
Posted: Tuesday, February 4, 2020

Researchers have discovered that TANK binding kinase 1 (TBK1)—an enzyme involved in innate immune response—appears to be a target in clear cell renal cell carcinomas that have a loss of the critical tumor-suppressor gene, von Hippel-Lindau (VHL). Qing Zhang, PhD, of the University of Texas Southwestern Medical Center, Dallas, and colleagues established that TBK1 is hyperactivated by VHL loss or hypoxia in cancer cells. “We found that inhibiting TBK1 activity slowed or blocked cancer cell growth,” stated Dr. Zhang in a UT Southwestern Medical Center  press release. The study findings were published in Cancer Discovery.

Dr. Zhang and colleagues observed that tumors from patients with VHL-deficient clear cell renal cell carcinomas displayed elevated TBK1 phosphorylation. They also discovered that loss of TBK1 by genetic ablation, pharmacologic inhibition, or a Cereblon-based proteolysis targeting chimera specifically inhibited VHL-deficient clear cell renal cell carcinoma cell growth while leaving healthy VHL wild-type cells unaffected. “That indicates this strategy holds the potential for selective lethality,” explained Dr. Zhang.

TBK1’s role in cancer appears to be distinct from the enzyme’s function in the immune system. “We believe targeting and manipulating TBK1 activity—possibly with drugs already under investigation for other cancers—may benefit patients with other forms of cancer,” concluded Dr. Zhang.

Disclosure: For full disclosures of the study authors, visit cancerdiscovery.aacrjournals.org.



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