An Integrated Strategy to Target the KRAS Oncogene System
Abstract
Approximately 40% of colorectal cancer patients have a KRAS or NRAS mutation and are therefore insensitive to treatment with EGFR inhibitors like cetuximab and panitumumab. We have recently uncovered a mechanism that explains why one specific KRAS mutation, KRAS G13D, retains sensitivity to EGFR inhibitors. This discovery was aided by a computational model of the RAS signaling network that mathematically describes each of the different types of RAS mutations in terms of their specific biochemical properties. This work was also aided by a panel of colon cancer cell lines that vary only in which KRAS mutation is expressed. This project aims to utilize both the computational and experimental models to uncover the critical variables that determine whether a cell is responsive or resistant to EGFR inhibitors. We hypothesize that drugs that modulate these biological variables would be able to convert the 40% of EGFR inhibitor-resistant colorectal cancers into EGFR inhibitor sensitive colorectal cancers. The Principal Investigator (PI) is a physician-scientist who, in addition to having been trained in medicine and cancer research, has also trained in mathematics. The mathematical training allows the lab to utilize emerging, data-intensive methods that can uncover important biological relationships that are inherently difficult to identify without computational methods. The career goals of the PI are to expedite improvements in cancer patient treatment through the integration of mathematical methods into cancer research. The proposed research program integrates both mathematical and computational methods to target the most common activating mutation that drives human cancer. Approximately 40% of all colorectal cancer patients have a KRAS or NRAS mutation and are thus insensitive to EGFR inhibitors. Our strategy, if successful, could give this large fraction of cancer patients a new treatment option. EGFR inhibitors are not curative, but do provide additional months of survival. The projected time for the research proposed to benefit cancer patients would depend largely on what co-targeting strategies are identified. If co-targeting strategies are uncovered that would utilize currently US Food and Drug Administration (FDA)-approved agents, physicians would have the ability to pursue off-label use of the treatment soon after learning of the combination after consultation with patients about the risks. If co-targeting strategies are uncovered that would involve targeting proteins for which there are no FDA approved agents, the drug development process could begin immediately, but the drug development process takes many years. Colorectal cancer has been reported to be the third most common cancer among active duty military Service members. Although colorectal cancer can influence people of all ages, colorectal cancer primarily affects individuals older than 50. Thus, this research is more likely to benefit Veterans and current military members after they complete their Service.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010538
Entities
People
- Edward Stites
Organizations
- Salk Institute for Biological Studies
- United States Army