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

Cell Death & Differentiation (2025)Cite this article

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Abstract

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.

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Fig. 1: ScRNA-seq data indicate that BCKDK is involved in lung cancer initiation.
Fig. 2: BCKDK promotes the malignant progression of lung cancer.
Fig. 3: BCKDK promotes the expression of MYC.
Fig. 4: MYC contributes to BCKDK mediated lung tumorigenesis.
Fig. 5: BCKDK promotes aerobic glycolysis through the MYC/HK2 axis in lung cancer.
Fig. 6: BCKDK regulates MYC expression through BCLAF1.
Fig. 7: BCKDK promotes MYC transcription by phosphorylating the S285 site of BCLAF1.
Fig. 8: BCKDK promotes Trametinib resistance both in vitro and in vivo.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We would like to thank the research sharing platform of Tianjin Medical University for providing experimental assistance.

Funding

This work was funded by the National Key Technologies R&D Program (intergovernmental international innovation cooperation, 2018YFE0102000) and the National Natural Science Foundation of China (NSFC) Program (82173199).

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Authors and Affiliations

  1. Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Key Laboratory of Cellular and Molecular Immunology, Tianjin Medical University, Tianjin, 300070, China

    Hao Wu, Jiajia Yang, Yawen Xiao, Ran Liu, Xinrui Zhang, Yuting Zhang, Zhi Yao & Junqiang Lv

  2. Department of Medical Laboratory, Tianjin Hospital, Tianjin University, Jiefang Nan Road 406, Hexi District, Tianjin, 300211, China

    Zixia Yang

  3. Kangzhe Pharmaceutical Technology Development Company, Ltd., Tianjin, 300110, China

    Jing Jia & Zheng Fu

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Contributions

HW performed and analyzed all bioinformatic analyses and experiments. JJY participated in most of the experiments. ZXY was responsible for tissue microarray acquisition and immunohistochemistry experiments. YWX contributed to data acquisition and analysis. RL, JJ, XRZ and YTZ supported some of the experiments. HW wrote the manuscript. ZY and ZF provided critical resources and financial support. JQL conceptualized the project, supervised the study, and secured funding.

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Correspondence to Zheng Fu, Zhi Yao or Junqiang Lv.

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The authors declare no competing interests.

Ethics

Human tumor tissues were sourced from Tianjin Medical University General Hospital. Informed consent was obtained from all patients before participation. The study involving human subjects was approved by the Ethics Committee of Tianjin Medical University General Hospital and conducted in compliance with the Declaration of Helsinki. Additionally, all animal experiments were reviewed and approved by the Animal Ethics Committee of Tianjin Medical University (TMUaMEC2024057) and performed in accordance with its legal requirements.

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Wu, H., Yang, J., Yang, Z. et al. Targeting the BCKDK/BCLAF1/MYC/HK2 axis to alter aerobic glycolysis and overcome Trametinib resistance in lung cancer. Cell Death Differ (2025). https://doi.org/10.1038/s41418-025-01531-6

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