Targeting PCK1 to overcome CDK4/6 inhibitor resistance for breast cancer therapy.

Phosphoenolpyruvate carboxykinase 1 (PCK1) is known for its role in gluconeogenesis and the regulation of PCK1 expression was shown to associate with oncogenic activity in pancreatic and colorectal cancers. However, in different cancer types such as liver cancer, PCK1 could function as a tumor suppressor, rendering complication for targeted therapy. In this study, we used breast cancer model to delineate its involvement in malignancy, we found PCK1 associated with oncogenic function to promotes cell proliferation, enhances colony formation, and stimulates DNA synthesis in breast cancer. Mechanistically, we found that PCK1 interacts with Cyclin D3, establishing a positive correlation between PCK1 and Cyclin D3 in clinical breast cancer tissues. Cyclin D3 forms a complex with CDK4/6, implicated in the development of resistance to CDK4/6 inhibitors. We identified PCK1 as a key factor in this resistance. Through an extensive screening process, we identified everolimus and auranofin as inhibitors of PCK1. We found that these drugs, in combination with CDK4/6 inhibitors, exhibit a synergistic effect in suppressing breast cancer. These findings reveal the connection between PCK1 and CDK4/6 inhibitor resistance, offering the possibility for improved treatment options for breast cancer. Interestingly, we also found PCK1 and Cyclin D3 interaction in pancreatic cancer, similar to that in breast cancer, but not in liver cancer. Thus, the results may resolve the puzzle for the role of PCK1 in tumor-promoting or -suppressive role in different cancer types.