Structural and Biochemical Differences Between the Most Common Pancreatic and Colorectal Cancer G12D and G12V Mutants of K-Ras
Abstract
Mr. Banerjee is a graduate student in the Department of Chemistry at the University of Illinois at Chicago. He is being trained as a structural biologist whose long-term career goal is to become an independent cancer researcher. Mr. Banerjee’s training in solution nuclear magnetic resonance (NMR) allows him to study flexible biomolecules that constantly alter their conformation. His research aims to address fundamental concepts in pancreatic and colorectal cancer biology and seeks to propose a potential cure for these deadly cancer types. He intends to pursue postdoctoral research in cancer biology and to enhance his knowledge of cell biology and medicinal chemistry. The objective of this research is to explore the possibility that personalized treatments can be found based on specific mutations in pancreatic and colorectal cancer. K-Ras is a small 21 KDa GTPase that is frequently mutated in these malignancies. K-Ras is active when GTP-bound and becomes inactivated after GTP is hydrolyzed to GDP. Oncogenic mutations occur mostly at position 12 of the N-terminal region of the protein and inhibit GTP hydrolysis. Most prevalent mutations include glycine to aspartic acid and glycine to valine substitutions. These mutations activate different signaling pathways and lead to distinct phenotypic characteristics of cancer. The glycine to valine mutation often results in resistance to chemotherapy and high metastatic potential. Unfortunately, multiple attempts to inhibit K-Ras in these cancers have failed primarily because of the lack of deep pockets for drug binding within this biomolecule. Mr. Banerjee found that the valine mutant (G12V) but not the aspartate mutant in the GDP state samples the “active-like” conformation and interacts with a ubiquitous calcium regulator protein calmodulin with high affinity. The K-Ras-calmodulin complex promotes stem cell-like properties in cancer cells and may be responsible for chemotherapy resistance. Hence, inhibiting this complex would provide an avenue for a novel therapeutic strategy to treat pancreatic and colorectal cancer. Research on the structural details of this protein-protein complex can aid in the development of anti-cancer drugs targeting this complex instead of the K-Ras mutant. This therapeutic strategy would be personalized and highly specific. It would require identification of patients with G12V K-Ras-driven cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710509
Entities
People
- Avik Banerjee
Organizations
- United States Army
- University of Illinois at Chicago