Integrated computational and preclinical evaluation of drug repurposing candidates for KRAS-mutant non-small cell lung cancer
TL;DR
Findings support nilotinib as a promising therapeutic candidate for KRAS-mutant NSCLC after a structure-based drug repurposing approach was employed to screen FDA-approved compounds targeting key regulators to the MAPK signalling pathway.
Abstract
KRAS mutations, particularly KRAS G12C, pose significant therapeutic challenges in non-small cell lung cancer (NSCLC) due to limited inhibitor efficacy and rapid resistance. Drug repurposing offers a time and cost-effective strategy to identify alternative therapeutic options targeting KRAS-driven signalling. A structure-based drug repurposing approach was employed to screen FDA-approved compounds targeting key regulators to the MAPK signalling pathway and computationally modelled for potential engagement with the KRAS G12C switch-II pocket. Computational analyses including virtual screening, molecular docking, and molecular dynamics simulations were used to evaluate binding affinity, stability and potential protein-ligand interactions. Lead candidates were subsequently validated using in vitro functional assays, ex ovo chorioallantoic membrane (CAM) and in vivo chemical induced lung carcinoma model. Computational analyses identified nilotinib and risperidone as high affinity candidates across MAPK pathway targets. Functional assays confirmed that nilotinib markedly reduced NSCLC cell viability, colony formation and angiogenesis, while inhibiting cell migration and inducing apoptosis. In vivo, nilotinib significantly lowered tumor burden and modulated immune and inflammatory profiles in a chemically induced murine lung carcinoma. These findings support nilotinib as a promising therapeutic candidate for KRAS-mutant NSCLC. Further studies involving target-engagement assays, pathway-validation experiments and genetically defined KRAS-G12C driven models are warranted to establish its precise mechanism of action.