In addition, the basal up-regulated AKT pathway was correlated with lower efficacy of GC1118, and our preliminary, promising results indicated that GC1118 combined with the PI3K/mTOR/AKT inhibitor BEZ-235 showed improved antitumor effects on KRAS-mutant tumors with intrinsically high AKT activity with favorable safety, encouraging further studies using novel therapeutic combinations to treat clinically-aggressive KRAS-mutant CRC showing elevated ratios of high- to low-affinity EGFR ligands and PI3K/mTOR/AKT signaling (Figure 6). The gene discussed is PIK3CA; the disease is colorectal carcinoma.