The researchers discovered a mechanism by which a gene, called TNK1, becomes an oncogenic driver in cancer. TNK1 is present in all cells, but when mutated, it becomes dangerous and able to convert normal cells into cancer cells. This puts TNK1 in a select category of cancer driver genes.

"You can think of cancer drivers as the engine that makes cancer grow and progress," said the senior author. The researchers also figured out how mutations in the TNK1 gene cause cancer. It's a significant discovery considering only a handful of other drivers like TNK1 are known to scientists.

"One of the greatest modern challenges of cancer research is identifying new cancer drivers because each one holds the key to a potentially much more effective cancer treatment," said the author.

For years, the senior author has studied a cancer-promoting protein called 14-3-3 that exists at unusually high levels within cancer cells. Six years ago, the author identified TNK1 as an interacting partner of 14-3-3. The research has led to a greater understanding of TNK1 and how it acts as a cancer driver.
 
After identifying TNK1 six years ago, the researchers began working to understand its properties with the goal of designing and developing a new drug to treat tumors caused by TNK1.

The authors discovered a MARK-mediated phosphorylation on TNK1 at S502 that promotes an interaction between TNK1 and 14-3-3, which sequesters TNK1 and inhibits its kinase activity. Conversely, the release of TNK1 from 14-3-3 allows TNK1 to cluster in ubiquitin-rich puncta and become active. Active TNK1 induces growth factor-independent proliferation of lymphoid cells in cell culture and mouse models.

One unusual feature of TNK1 is a ubiquitin-association domain (UBA) on its C-terminus. The researchers characterize the TNK1 UBA, which has high affinity for poly-ubiquitin. Point mutations that disrupt ubiquitin binding inhibit TNK1 activity. These data suggest a mechanism in which TNK1 toggles between 14-3-3-bound (inactive) and ubiquitin-bound (active) states.  

The scientists started designing compounds that would target TNK1 in cancer cells. Through computer modeling and structure-based rational design, they continued to test and then optimize how this compound would react.

The pre-clinical results for the drug, called TP-5801, are extremely promising. TNK1 inhibitor, TP-5801 shows nanomolar potency against TNK1-transformed cells and suppresses tumor growth. The compound has passed FDA-required steps and is now ready for what's called a first-in-human study or phase 1 clinical trial.

https://www.nature.com/articles/s41467-021-25622-3

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Ftnk1-is-a-ubiquitin&filter=22