It is known that cancer involves uncontrolled cell growth and that the signaling pathway that regulates body size, known as Hippo, is also involved in cancer. In addition, it is known that an important role in cancer development plays YAP protein that controls many types of tumors. Now, researchers from Children's Hospital Boston have decided constant challenge: how to apply this knowledge in the treatment. In a study published in Nature Communications November 16, they show that YAP operates mainly through NUAK2.
"Hippo signaling pathway, particularly YAP protein, it was hard to focus on drugs", - says senior researcher Fernando Camargo, Ph.D., program Boston Children's Stem Cell Research. "This is the first demonstration of" drug "molecule that can be targeted to tumors of any type caused by YAP".
Although the study is associated with liver cancer, the results may be important for many cases of breast cancer caused by YAP, carcinoma of the head and neck, pancreatic cancer, Ovarian cancer and squamous cell skin cancer, adds Camargo. The team hopes to test this in future studies.
Search drug targets cancer
YAP - is a transcription factor, type of target, which is considered the "inflexible" because transcription factors are not structural features that allow the drug to contact them. But YAP, in turn, regulates the activity of many other genes, and Wei-Jian Yuan, Ph.D., at the Camargo lab aimed at identifying these genes, hoping to find something else to achieve the goal.
Using cell lines and human liver cancer mouse model of liver cancer, Yuan combined several tests to zero in on what affects the downstream genes of YAP. She found 14, then narrowed the search to the kinases, enzymes that are particularly sensitive to drugs. And I found only one: NUAK2.
Further experiments showed that NUAK2 (also known as sucrose nonfermenting [SNF1] -like kinase or SNARK) is critical to the YAP-stimulated growth of human cancer cell lines and cancer cell proliferation in mice.
Finally, they showed that malomolekulyarnoe compound which inactivates NUAK2, severely restricts the proliferation of cancer cells controlled YAP, and leads to an increase in the liver.
Targeting NUAK2 has the additional advantage, says Camargo, who is also associated with the Children's Cancer Dana-Farber / Boston Cancer and Blood Disorders Center. "He goes back to activate itself YAP, NUAK2 therefore further reduces inhibition activity YAP».
Yuan and colleagues now hope to expand their findings.
"We know what works NUAK2 inhibition in liver cancer Now we need to find out whether the same mechanism plays in other types of cancer,." - says Camargo.
They also plan to modify their small molecule initially synthesized in the laboratory Nathanael Gray, Ph.D., at the Institute Dana-Farber Cancer.
"We want to see if we can make the composition more selective, - says Yuan, the first author of the paper." It has other non-specific target, so we need to change it to make it usable ".