Targeting the BCKDK/BCLAF1/MYC/HK2 axis to alter aerobic glycolysis and overcome Trametinib resistance in lung cancer.

The protein branched-chain ketoacid dehydrogenase kinase (BCKDK), which regulates the metabolism of branched-chain amino acids, has recently been implicated in tumor progression. However, the role of BCKDK in lung cancer remains largely unexplored. In this study, we explored the mechanisms by which BCKDK influences lung cancer progression and contributes to drug resistance. By integrating single-cell RNA and bulk RNA sequencing data from lung cancer patients, we identified BCKDK as a novel gene related to malignant epithelial cells, involved in tumor initiation and associated with poor patient prognosis. Subsequently, through a series of molecular biology experiments, we demonstrated that BCKDK promotes aerobic glycolysis, Trametinib resistance, and tumor progression in lung cancer by upregulating MYC transcription. Mechanistically, BCKDK interacts with BCLAF1 to promote its phosphorylation at the serine 285 site. This modification facilitates BCLAF1 binding to the MYC promoter, thereby enhancing MYC transcription. Subsequently, elevated MYC levels upregulate hexokinase 2, promoting aerobic glycolysis and lung cancer progression. In addition, the elevated glycolysis product, lactate, promotes Trametinib resistance by upregulating the ABC transporters. Taken together, our data identify BCKDK as a novel regulator of aerobic glycolysis that promotes lung cancer progression and Trametinib resistance through the BCKDK/BCLAF1/MYC/HK2 axis. Targeting BCKDK in combination with Trametinib may offer a promising treatment for lung cancer. Graphical representation of the BCKDK/BCLAF1/MYC/HK2 axis and its role in Trametinib resistance and lung cancer progression. Created with BioRender.com.