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. KRAS mutations 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 between AKT1/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 of AKT1 E17K, E49K and L52R mutations, as well as CTNNB1 T41A, S45F and S33P mutations compared with that of respective WT proteins. AKT1/CTNNB1 mutations 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/CTNNB1 mutations may be used as an important predictive biomarker in CRC treatment.

Integrated Analysis of Necroptosis-Related Genes for Prognosis, Immune Microenvironment Infiltration, and Drug Sensitivity in Colon Cancer

“…The top 20 genes with the highest mutation rates in both scoring subgroups were identified, and all of these genes had mutation rates above 10%. Previous studies have shown that KRAS mutation can act as a biomarker of EGFR-targeted monoclonal antibody resistance in colon cancer patients and is associated with metastasis and poor prognosis ( 36 , 37 ). In our study, KRAS mutation frequency ranked fourth in both high and low NRS-score groups.…”

NEBL and AKT1 maybe new targets to eliminate the colorectal cancer cells resistance to oncolytic effect of vesicular stomatitis virus M-protein

“…As the second hypothesis, SW480 cells have several mutations in the TP53 gene while HCT116 harbored WT TP53. 38 , 41 Moreover, HCT116 showed lower BCL-2 family activity compared with SW480 cells. 42 Furthermore, previous research has reported the M-protein effects on BCL suppression.…”

Emerging actionable targets to treat therapy-resistant colorectal cancers

“…Recently, Vitiello et al [112] used four different KRAS-mut CRC cell lines rendered resistant to a combination of cetuximab and refametinib (a selective MEK-inhibitor) and demonstrated that PI3K-AKT pathway activation acts as an escape mechanism in this setting. They showed that autocrine loops and heterodimerization of multiple receptors lead to the activation of several receptor tyrosine kinase, such as ERBB2, ERBB3 and IGF1R, whose signaling onto the PI3K/AKT pathway allows to bypass the block imposed by the double targeting of EGFR and MEK [112] . The effect on the response to cetuximab in the setting of the three most common AKT1 activating mutations found in CRC patients (i.e., E17K, E49K, and L52R) was recently investigated by overexpressing them in a cetuximab-sensitive KRAS-wt CRC cell line.…”

“…Interestingly, all of them impaired the cytotoxic response not only toward cetuximab but also to chemotherapy. In addition, also the most common mutations of CTNNB1 (i.e., T41A, S45F, and S33P) were found to sustain resistance to the same agents [ 113 ] . These data indicate that possible therapeutic strategies to counteract the resistance to EGFR-targeted therapy would therefore be the use of inhibitors of the PI3K/AKT pathway.…”