Research explores why patients with mutated KRAS genes in tumor cells are sensitive to cetuximab.
Researchers have combined computational biology with experimental investigations to discover for the first time, the mechanism that drives some colorectal cancer patients to respond to cetuximab, according to a new study from the Salk Institute. These findings, published in Science Signaling, may help doctors identify more effective targeted treatment plans for people diagnosed with colorectal cancer.
Approximately 40% of patients with colorectal cancer have a mutated KRAS gene in cells in their tumors. Most KRAS mutants make it so the patient cannot benefit from the chemotherapy drug, cetuximab; however, patients with the KRAS G13D mutation are exceptions and have appeared to respond to the drug. The mechanism of action has historically been unknown, so cetuximab is not commonly used on patients with KRAS G13D. Doctors are hesitant to prescribe a drug without a known mechanism due to the risks of interaction with other medications or unforeseen adverse events. Therefore, the researchers’ sought to reveal why these tumors are sensitive to cetuximab.
The study authors first used computational models to simulate complex reactions and tease out biochemical differences between healthy and mutant genes based on the biochemical understanding of each process and previous clinical trial data. Because of this process, the researchers then knew where to look in their laboratory tests to identify and quantify the molecular mechanism that explains why KRAS G13D patients respond differently. The researchers then replicated their findings across 3 genetically distinct cell lines.
In a cell with no KRAS mutations, a known tumor suppressor called neurofibromin controls healthy KRAS proteins; however, most KRAS mutations are overly active and cannot be controlled by neurofibromin. When mutated KRAS is present, neurofibromin attempts to control it at the expense of controlling the healthy KRAS, according to the study.
The scientists discovered that although KRAS G13D is overly active, the neurofibromin does not know to suppress it. Therefore, neurofibromin can still keep the healthy KRAS under control. The researchers demonstrated that cetuximab will only work to suppress tumors as long as there is neurofibromin available to suppress the activity of healthy KRAS.
The study authors plan to examine the mechanisms of more KRAS gene mutation variants that do not bind to neurofibromin, as patients with these variants may also benefit from taking cetuximab.