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Understanding KRAS Mutations and Treatment Choice in Colorectal Cancer

By: Lauren Harrison, MS
Posted: Tuesday, October 29, 2019

A new study used systems approaches to enable mechanism-based interference in genomic medicine and identified a way to choose patients for selective therapeutic targets. The team focused on patients with colorectal cancer and used computational biology to understand why patients with KRAS G31D mutations benefit from the EGFR-blocking antibody cetuximab. Edward Stites, MD, PhD, of the Salk Institute for Biological Sciences in La Jolla, California, and colleagues published this work in Science Signaling.

“This study has direct clinical implications because now doctors can start prescribing this effective drug to colorectal cancer patients with this mutation immediately,” said Dr. Stites in a Salk press release. “Doctors could sequence the gene to find out if the patient has this KRAS G13D variant, and if they do, then doctors could confidently prescribe cetuximab. That’s important, because it will give many cancer patients a new treatment option.”

Researchers used a computational model to simulate RAS signaling. They were able to find biochemical differences between the healthy and mutated genes based on the biochemical understanding of various RAS-signaling processes and clinical trial data. The team found that the three most common mutations in KRAS were able to create different sensitivities to EGFR inhibition.

Via their computational method, a nonintuitive mutant-specific dependency of wild-type RAS activation by EGFR was found. This dependency is determined by the interaction strength between KRAS and the tumor-suppressor neurofibromin. KRAS mutants that strongly interacted with neurofibromin competitively inhibited the molecule, leading to wild-type RAS activation in an EGFR-independent manner. KRAS G13D, however, weakly interacted with and could not inhibit neurofibromin, so KRAS G13D–mutant cells remained dependent on EGFR for wild-type RAS activity. According to the investigators, this EGFR dependence conferred these cells’ sensitivity to cetuximab.

Disclosure: The study authors’ disclosure information can be found at stke.sciencemag.org.



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