A new study has identified an unexpected role for the WEE1 kinase in helping esophageal adenocarcinoma survive and resist chemotherapy. Researchers found that WEE1, normally known for regulating the cell cycle in the nucleus, is abnormally active in the cytoplasm of esophageal cancer cells, where it helps stabilize the cancer-driving protein c-MYC.
The study showed that WEE1 blocks the activity of GSK3β, a protein that normally marks c-MYC for destruction. By protecting c-MYC, WEE1 promotes tumor growth, cancer stem cell features, and drug resistance through activation of the MRP1 drug efflux pump.
When researchers inhibited WEE1 using the drug Adavosertib, cancer cells lost c-MYC stability, retained more chemotherapy drugs, and became more sensitive to platinum-based treatments.
A large drug screening study identified Panobinostat as a strong partner for WEE1 inhibition. The combination caused major tumor regression in organoid and mouse models without excessive toxicity, suggesting a potential new treatment strategy for aggressive esophageal cancer.