EGFR and colorectal cancer: • Definiton of patient-overarching colorectal cancer cell clusters characterized by differential activities of oncogenic signaling pathways such as mitogen-activated protein kinase and oncogenic traits such as replication stress.• CRC cell development trajectories follow the MAPK pathway in tumor organoids.• The targeting of EGFR-BRAF-MEK in tumor organoids depends on acquired KRAS/BRAF mutations and induced cellular plasticity rather than the default developmental trajectory that affects signal transduction and gene expression.