Suppression of Wnt/β-catenin and RAS/ERK pathways provides a therapeutic strategy for gemcitabine-resistant pancreatic cancer

Pancreatic cancer is a major malignant tumor without an effective treatment. KRAS mutations occur in 90% of the pancreatic cancer patients and are a major obstacle for treatment of pancreatic cancer. Pancreatic cancer patients have been treated with limited chemotherapeutic agents such as gemcitabine. However, patients often develop resistance to gemcitabine that is attributed to KRAS mutations. Gemcitabine treatment activates both the Wnt/I3-catenin and RAS/ERK pathways. These signaling pathways are also activated in the gemcitabine-resistant pancreatic cancer cell lines, suggesting that they play an important role in gemcitabine resistance in pancreatic cancer. The gemcitabine-resistant cell lines show enhanced migratory and invasive capabilities than their parental lines. Therefore, we investigated the effects of a small molecule, KYA1797K that degrades both beta-catenin and RAS, on pancreatic cancer. KYA1797K decreased the expression level of both beta-catenin and KRAS in pancreatic cancer cell lines expressing either wild-type or mutant KRAS. It also suppressed migration and invasion of gemcitabineresistant and parental pancreatic cancer cells. Overall, we demonstrated that inhibiting the Wnt/beta-catenin and RAS/ERK pathways by destabilizing beta-catenin and RAS could be a therapeutic approach to overcome gemcitabine resistance in pancreatic cancer. (C) 2021 The Authors. Published by Elsevier Inc.

Automated summary

Pancreatic cancer often presents with KRAS mutations, hindering treatment effectiveness. Chemotherapeutic agents like gemcitabine easily lead to resistance. Research suggests that destabilizing beta-catenin and RAS protein can suppress migration and invasion, offering a potential solution for overcoming gemcitabine resistance.