Identification of AKT1/β-catenin mutations conferring cetuximab and chemotherapeutic drug resistance in colorectal cancer treatment

Abstract

In anticancer therapy, the effectiveness of therapeutics is limited by mutations causing drug resistance.KRASmutations are the only determinant for cetuximab resistance in patients with colorectal cancer(CRC). However, cetuximab treatment has not been fully successful in the majority of patients with wild‑type(WT)KRAS. Therefore, it is important to determine new predictive mutations in CRC treatment. In the present study, the association betweenAKT1/β-catenin (CTNNB1) mutations with the drug resistance to cetuximab and other chemotherapeutics used in the CRC treatment was investigated by using site‑directed mutagenesis, transfection, western blotting, and cell proliferation inhibition assay. Cetuximab resistance was higher in the presence ofAKT1E17K, E49K, and L52R mutations, as well asCTNNB1T41A, S45F, and S33P mutations compared with that of respective WT proteins.AKT1/CTNNB1mutations were also associated with oxaliplatin, irinotecan, SN‑38, and 5‑fluorouracil resistance. Furthermore, mutant cell viability in oxaliplatin treatment was more effectively inhibited compared with that of the other chemotherapeutic drugs. In conclusion,AKT1/CTNNB1mutations may be used as an important predictive biomarker in CRC treatment.