Mutations in AGC kinase motif linked to colorectal cancer growth

Cancer spreads throughout the human body in cunning, almost militaristic, ways. For instance, it may possibly manipulate our genetic make-up, take over specific cell-to-cell signaling processes, and mutate key enzymes to advertise tumor growth, resist therapies, and hasten its spread from the unique site to the bloodstream or other organs.

Enzyme mutations have been of great interest to scientists who study cancer. Scientists within the Liu and Tan labs at UNC’s Lineberger Comprehensive Cancer Center have been studying mutations of enzyme recognition motifs in substrates, which can more faithfully reflect enzyme function with the potential to seek out recent targets or directions for cancer treatment.

We expect understanding the roles of mutations on enzyme substrates, as an alternative of the enzyme as a complete, may help to enhance efficacy of targeted therapies, especially for enzymes which have each oncogenic and tumor suppressive function through controlling distinct subsets of substrates.”

Jianfeng Chen, PhD, first creator and postdoctoral fellow within the Liu lab, UNC Department of Biochemistry and Biophysics

Their results were published in Journal of Experimental Medicine on June 29, 2023.

AGC kinase motif mutations

Using the developed algorithm and knowledge from The Cancer Genome Atlas (TCGA), they found that the best rate of mutation occurs within the AGC kinase motif called RxRxxS/T. RxRxxS/T is a brief, recurring pattern that’s shared among the many 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 present itself more benefits for tumor growth and survival,” said Pengda Liu, PhD, who’s an associate professor of biochemistry and biophysics.

A brand new mechanism for colorectal cancer

The Liu and Tan groups conducted a validation study on the AGC kinase motif mutations related to 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 found that colon cancer “hijacks” BUD13 mutations, a protein-coding gene, to sidestep the phosphorylation which might be carried out by AGC kinase. Colon cancer ultimately prefers these BUD13 mutations since it gains an extra profit by inactivating an E3 ligase called Fbw7. “Turning off” Fbw7, an important tumor suppressor, causes a rise in tumor growth and therapy resistance.

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

“It’s exciting to teasing out various kinds of somatic mutations and we’re glad to supply this publicly available resources to cancer research community,” said Xianming Tan, PhD, who’s a research associate professor within the Department of Biostatistics within the Gillings School of Public Health and the Lineberger Comprehensive Cancer Center.