The idea was simple: find the faulty signals that drive cancerous growth in cells, and block them. But what University of North Carolina Lineberger Comprehensive Cancer Center researcher Pengda Liu, PhD, has discovered, when it comes to cancer, even straightforward concepts can become complicated.
“When you find a target and inhibit it, you find the cancer is smart and it finds a bypass or another pathway,” said Liu, who is an assistant professor in the UNC School of Medicine Department of Biochemistry & Biophysics.
In a study published in the journal Nature Communications, Liu, Shelton Earp, MD, director of UNC Lineberger and the Lineberger Professor of Cancer Research, and their collaborators report discoveries about a key signaling pathway that can be hyperactive in kidney cancer. The study provides insights about the mechanism behind hypearctivation of Akt, a signal that plays an “indispensable” role in cell proliferation, survival and metabolism. Virtually all solid tumors have hyperactivation of Akt, researchers reported.
When cells self-destruct, they can send out warning signals to adjacent cells. These signals, including signals that are dispersed from a type of cell self-destruction known as “apoptosis,”, initiate self-preservation tactics – triggering neighboring cells to survive. This process can aid in cancer cells’ ability to develop resistance to treatments, Liu said.
In their latest study, researchers, working with laboratory models of kidney cancer, discovered that the SAV1 molecule helps keep Akt inactive. The researchers also found that to activate Akt, the MERTK molecule releases SAV1 from Akt.
“This discovery shows that MERTK activates Akt by releasing an Akt inhibitor, rather than directly activating Akt,” Liu said.
The finding has a number of potential implications.
First, it provides important insights about an experimental cancer therapeutic that is in development. UNC Lineberger researchers have been involved in efforts to develop a MERTK signal inhibitor. This compound is now in early-stage clinical trials.
The new findings offer clues into what researchers should look for to ensure that inhibitors will work. In addition to using this MERTK inhibitor, researchers now know that SAV1 needs to be in place to prevent hyperactivation of Akt. The researchers also found that genetic mutations that affect SAV1 function can allow for Akt hyperactivation – a wrinkle that could provide insight as to lack of treatment response.
Liu said researchers plan further studies of this mechanism. They also want to investigate whether they can target multiple parts of this pathway in kidney cancer to prevent cancerous growth.
“Cancer is smart, and there is much more that we need to learn to combat this disease,” Liu said.
In addition to Liu and Earp, other authors included Yao Jiang, Yanqiong Zhang, Janet Y. Leung, Cheng Fan, Konstantin I. Popov, Siyuan Su, Jiayi Qian, Xiaodong Wong, Alisha Holtzhausen, Eric Ubil, Yang Xiang, Ian Davis, Nikolay V. Dokholyan, Gang Wu, Charles M. Perou, and William Y. Kim.
Conflict of interest: Earp is a founder of Meryx, a UNC startup, that is developing small molecule inhibitors for MERTK. Earp and Xiaodong Wong own stock in Meryx.
The study was supported by the National Institutes of Health, the UNC IBM Junior Faculty Development Award, the V Scholar Research Grant, and University Cancer Research Fund.