A mechanism for the response of KRAS(G13D) expressing colorectal cancers to EGFR inhibitors

Previous analysis of Phase 3 clinical trial data for colorectal cancer patients treated with cetuximab revealed that patients harboring a KRAS mutation did not benefit from treatment. This finding set the stage for one of the first examples of cancer personalized medicine. Confusingly, patients with a Glycine to Aspartic Acid mutation at amino acid 13 of KRAS (KRAS(G13D)) appeared to respond positively to cetuximab, suggesting this mutation is an exception to the rule that KRAS mutations confer resistance to Epidermal Growth Factor Receptor (EGFR) inhibitors. Oncologists have stated that the mechanism that explains why the KRAS(G13D) mutation is an exception should be identified before KRAS(G13D) colorectal cancer patients should be treated differently. We have recently elucidated this mechanism using mathematical modeling of the KRAS biochemical system coupled with experimental biology. The mechanism we revealed involves a cetuximab-mediated reduction in HRAS and NRAS signaling within KRAS(G13D) cancer cells, owing to impaired binding of KRAS(G13D) to the tumor suppressor, Neurofibromin (NF1).