Mechanism to understand role of mutations on enzyme

Cancer spreads in devious, almost military ways across the human body. It may, for example, alter our genetic make-up, take over certain cell-to-cell signalling mechanisms, and change essential enzymes to enhance tumour development, resistance to medicines, and expedite spread from the initial location to the bloodstream or other organs.

Enzyme mutations have piqued the curiosity of cancer researchers. Scientists in the Liu and Tan laboratories at UNC's Lineberger Comprehensive Cancer Centre have been examining mutations of enzyme recognition patterns in substrates, which may more faithfully represent enzyme activity and may lead to the discovery of novel targets or therapeutic approaches for cancer.

"We think understanding the roles of mutations on enzyme substrates, instead of the enzyme as a whole, may help to improve efficacy of targeted therapies, especially for enzymes that have both oncogenic and tumor suppressive function through controlling distinct subsets of substrates," said Jianfeng Chen, PhD, who is first author and a postdoctoral fellow in the Liu lab in the UNC Department of Biochemistry and Biophysics.

Their results were published in Journal of Experimental Medicine.

Using the developed algorithm and information from The Cancer Genome Atlas (TCGA), they found that the highest rate of mutation occurs in the AGC kinase motif called RxRxxS/T. RxRxxS/T is a short, recurring pattern that is shared among the AGC family of ~60 kinases. These enzymes play critical roles in metastasis, proliferation, drug resistance, and development.

"We found that cancer tried to either evade or create mutations on these RxRxxS/T motifs to give itself more advantages for tumor growth and survival," said Pengda Liu, PhD, who is an associate professor of biochemistry and biophysics.

The Liu and Tan groups conducted a validation study on the AGC kinase motif mutations associated with colorectal cancer, the second most lethal cancer and the third most prevalent malignant tumor worldwide. Currently, colorectal cancer has a 5-year survival rate of 12%.

They discovered that colon cancer "hijacks" BUD13 mutations, a protein-coding gene, to sidestep the phosphorylation that are carried out by AGC kinase. Colon cancer ultimately prefers these BUD13 mutations because it gains an additional benefit by inactivating an E3 ligase called Fbw7. "Turning off" Fbw7, a crucial tumor suppressor, causes an increase in tumor growth and therapy resistance.

In addition to their findings on Fbw7 inactivation, the research team also found that the BUD13 tumor cells were more susceptible to the inhibition of mTORC2 kinase, revealing a new, potential targeted therapy for colon cancer patients bearing that have the BUD13 mutation.

"It is exciting to teasing out different types of somatic mutations and we are glad to offer this publicly available resources to cancer research community," said Xianming Tan, PhD, who is a research associate professor in the Department of Biostatistics in the Gillings School of Public Health and the Lineberger Comprehensive Cancer Center.