In this study, we constructed a 3D tumor-spheroid-ECM (TSE) model by creating a tumor spheroid embedded within an ECM to monitor the drug responses of two invasive cell lines to AMG510, an inhibitor that targets the G12C-mutant KRAS expression and that has achieved responses in some patients with non–small cell lung cancer (NSCLC) or colorectal cancer (CRC). Here, KRAS is linked to colorectal carcinoma.