Immunohistochemical Localization of Sotorasib–Protein Conjugates in the Rat Gastrointestinal Tract

Abstract

Sotorasib is a molecularly targeted drug that exerts antitumor effects by selectively binding to KRAS G12C through a Michael addition reaction, irreversibly inhibiting KRAS. However, the frequent occurrence of adverse events, such as gastrointestinal and hepatic disorders, has raised major concerns. These toxicities are thought to arise from interactions between sotorasib and proteins other than KRAS in normal cells. In this study, we generated a specific antibody against sotorasib and established an immunohistochemical method capable of detecting sotorasib–protein conjugates. Using this technique, we clarified the localization of sotorasib–protein conjugates in the digestive tract of rats, including the duodenum, jejunum, ileum, and colon. Sotorasib–protein conjugates were strongly localized to the villous epithelial cells of the small intestine but were scarcely detected in the colon, highlighting regional differences. This study elucidates the localization of sotorasib–protein conjugates in the gastrointestinal tract of rats and provides important insights into the mechanisms underlying sotorasib-induced gastrointestinal disorders.