Molecular docking analysis reveals differential binding affinities of multiple classes of selective inhibitors towards cancer-associated KRAS mutants

KRAS is the most frequently mutated oncogene in solid cancers, and inhibitors that specifically target the KRAS-G12C mutant were recently approved for clinical use. The limited availability of experimental data pertaining to the sensitivity of KRAS-non-G12C mutants towards RAS inhibitors made it difficult to predict the response of KRAS-mutated cancers towards RAS-targeted therapies. The current study aims at evaluating sensitivity profiles of KRAS-non-G12C mutations towards clinically approved sotorasib and adagrasib, and experimental RAS inhibitors based on binding energies derived through molecular docking analysis. Computationally predicted sensitivities of KRAS mutants conformed with the available but limited experimental data, thus validating the usefulness of molecular docking approach in predicting clinical response towards RAS inhibitor treatment. Our results indicate differential sensitivity of KRAS mutants towards both clinical and experimental therapeutics; while certain mutants exhibited broad cross-resistance to most inhibitors, some mutants showed resistance towards specific inhibitors. These results thus suggest the potential of emergence of more resistance mutations in future towards RAS-targeted therapy and points to an urgent need to develop novel classes of inhibitors that are able to overcome both primary and secondary drug resistance.