This study aimed to investigate and improve the current standard of care chemotherapy combinations and optimize new targeted drug combinations for the improved treatment of colorectal carcinoma (CRC). We emphasize the relevance of various pre-clinical and clinical CRC systems for validation and clinical translation of drug combinations and establish a heterotypic 3D cell culture platform that can easily be adapted to improve other cancer cell cultures. We find that optimized low-dose cell-specific chemotherapy combinations did not improve the efficacy or the safety profile. We employed the phenotypically-driven therapeutically guided multidrug optimization (TGMO) technology and identified low-dose high-order cell-specific synergistic drug combinations of tyrosine kinase inhibitors. Mechanistically, multi-target inhibition orchestrated subtle multi-node regulation of cell signaling which predominantly converged on MAP kinase signaling and cell cycle arrest. We provide scientific evidence in vitro and in vivo of the value of personalized drug combinations to improve effective and selective CRC treatment.