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

Hasbal Çelikok G., Aksoy Sağırlı P., Altıparmak Ülbegi G., Can A.

Oncology Letters, cilt.21, sa.3, ss.209-218, 2021 (SCI-Expanded)

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 21 Sayı: 3
  • Basım Tarihi: 2021
  • Doi Numarası: 10.3992/ol.2021.12470
  • Dergi Adı: Oncology Letters
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, EMBASE
  • Sayfa Sayıları: ss.209-218
  • İstanbul Üniversitesi Adresli: Evet

Özet

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.