Carolina Scientific tion about how cancer cells adapt when a drug blocks a single pathway. Knowledge of this process helped to determine the mechanism behind what is known as kinome reprogramming, which occurs in breast cancer along with several other cancers. Kinome reprogramming can make some cancer treatments ineffective.1 Kinome reprogramming is the result of the inherent complexity of signaling within cells.1 In some cancer cells, blocking one type of kinase is not enough. When only one kinase is blocked, other kinases can be expressed that can block the drug used to treat the tumor. In effect, the cancer cell is taking what should be a road block – the inhibitor – and turning it into a detour. Knowledge of this mechanism made it possible to design a combination drug therapy to treat a group of tumors known as triple negative breast cancer (TNBC). The MIB/MS approach can be used to gather global information of kinome activity in other cancer cells. Dr. Johnson admits we are not there yet, but envisions using this information as a diagnostic tool and sees it as a step towards advancing personalized medicine. He stated, “You could actually do this in personalized medicine where you could understand an individual’s tumor, how it responded to therapy, and how you might change that therapy.”2 In fact, it is already being used to screen patients’ tumors at UNC Hospitals.2 In the future, tumors exhibiting kinome reprogramming could be detected by identifying biomarkers, molecules that are associated with a certain kinase pathway. This could mean that tumors that require a combination of drugs to be treated could be detected and treated right away instead of a physician providing a patient with ineffective drugs and allowing the tumor to grow
Figure 1. Summary of the MIB/MS process and a diagram of kinome activity. Red spheres indicate kinases whose activity increased relative to a baseline reading when treated with inhibitor. Blue spheres indicate kinases whose relative activity decreased. Image from Stuhlmiller, T.J.; Earp, H.S.; Johnson, G.L.; Clin Pharmacol Ther. 2014, 95(4) 414.
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“I still get pleasure when people in my lab do a really good experiment, and they’re really proud of it, and they need to realize that they may be the first person in the history of the world that has ever discovered that.” Dr. Johnson further. Starting out with the right treatment plan is critical when fighting cancer since mortality rates are significantly higher for patients whose treatments begin in later stages. The obvious complexity of kinase signaling networks demands a multifaceted approach of investigation. UNC is an ideal place for this research based on work being conducted in the pharmacy, medical, and public health schools, as well as by many researchers in fields like physics, computer science, and statistics that contribute to biomedical research. Dr. Johnson understands the importance of having experts in many disciplines in one place, explaining that he gets to interact with “basic scientists, translational scientists, clinical researchers, and people in the clinic… you can be right at the edge of development of new therapies.”2 It is not just making discoveries that Dr. Johnson finds rewarding, but also that his students go on to make important discoveries: “I still get pleasure when people in my lab do a really good experiment, and they’re really proud of it, and they need to realize that they may be the first person in the history of the world that has ever discovered that.”2 Dr. Johnson and his colleagues’ work highlight the importance of networking, both in cellular activity and in academia. Collaboration is the key to unraveling these highly integrated cellular signaling pathways and using this information to develop practical treatments. This research is representative of the field of pharmacology in general, too. It lies at the convergence of many fields, and thus pharmacological studies can have a broad impact on both pure research and applied health science. Using global kinome activity to develop better therapies demonstrates how esoteric knowledge gained from research can have a real impact on people’s lives. The work of Dr. Johnson’s lab helps bridge the gap between scientific research and medical application.
References
1. Stuhlmiller, T.J.; Earp, H.S.; Johnson, G.L.; Clin Pharmacol Ther. 2014, 95(4), 413-415. 2. Interview with Gary L. Johnson, Ph.D. 02/11/16.
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