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ALK fusion promotes metabolic reprogramming of cancer cells by transcriptionally upregulating PFKFB3

Oncogene volume 41, pages 4547–4559 (2022)Cite this article

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Abstract

Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase of the insulin receptor kinase subfamily, is activated in multiple cancer types through translocation or overexpression. Although several generations of ALK tyrosine kinase inhibitors (TKIs) have been developed for clinic use, drug resistance remains a major challenge. In this study, by quantitative proteomic approach, we identified the glycolytic regulatory enzyme, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), as a new target of ALK. Expression of PFKFB3 is highly dependent on ALK activity in ALK+ anaplastic large cell lymphoma and non-small-cell lung cancer (NSCLC) cells. Notably, ALK and PFKFB3 expressions exhibit significant correlation in clinic ALK+ NSCLC samples. We further demonstrated that ALK promotes PFKFB3 transcription through the downstream transcription factor STAT3. Upregulation of PFKFB3 by ALK is important for high glycolysis level as well as oncogenic activity of ALK+ lymphoma cells. Finally, targeting PFKFB3 by its inhibitor can overcome drug resistance in cells bearing TKI-resistant mutants of ALK. Collectively, our studies reveal a novel ALK–STAT3–PFKFB3 axis to promote cell proliferation and tumorigenesis, providing an alternative strategy for the treatment of ALK-positive tumors.

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Fig. 1: ALK-dependent upregulation of PFKFB3 in ALK+ cancer cells.
Fig. 2: PFKFB3 deficiency impaired glycolysis in ALK+ cancer cells.
Fig. 3: PFKFB3 is required for the oncogenic activity of ALK+ cancer cells.
Fig. 4: ALK promotes transcriptional expression of PFKFB3.
Fig. 5: ALK promotes PFKFB3 transcription through STAT3.
Fig. 6: ALK upregulates PFKFB3 to maintain glycolysis level in cancer cells.
Fig. 7: Ceritinib-resistant NPM::ALK mutants are sensitive to PFKFB3 inhibitor.

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Acknowledgements

We thank Xian Chen and Ling Xie (UNC) for their aid with mass spectrometry analysis, and Jian Jin (Mount Sinai) and Jing Liu (Cullgen Inc.) for providing ALK degrader compound. We appreciate Hongbin Ji and Zhen Qin (SIBCB, CAS) for their help in the analysis of ALK mutant tumors. We also thank Kuirong Luo (Zhongshan Hospital, Fudan University) for the help with the interpretation of IHC results. This work was supported by the NSFC grants (No. 82172595 and 81773190 to H-XY), the National Key Research and Development Project of China (No. 2018YFA0800304 to H-XY), Supporting Program of Health Commission of Fujian Province for junior talents (2021GGB03 to ML) and Shanghai Pujiang Program (2020PJD009 to ML). H-XY is also supported by the Innovative Research Team of High-level Local University in Shanghai.

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Author notes

  1. These authors contributed equally: Mengnan Hu, Ruoxuan Bao, Miao Lin.

Authors and Affiliations

  1. The Fifth People’s Hospital of Shanghai and the Molecular and Cell Biology Laboratory of the Institutes of Biomedical Sciences, Fudan University, Shanghai, China

    Mengnan Hu, Ruoxuan Bao, Yun Gao & Hai-Xin Yuan

  2. Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China

    Miao Lin

  3. Department of Thoracic Surgery, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China

    Miao Lin

  4. Cullgen (Shanghai) Inc., 230 Chuan Hong Road, Pu Dong New Area, Shanghai, China

    Xiao-Ran Han

  5. Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China

    Ying-Jie Ai

  6. Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, 92093, USA

    Kun-Liang Guan

  7. Cullgen Inc., 12671 High Bluff Drive, San Diego, CA, 92130, USA

    Yue Xiong

  8. Center for Novel Target and Therapeutic Intervention, Chongqing Medical University, Chongqing, China

    Hai-Xin Yuan

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Contributions

MNH, RXB, YX, K-LG, and H-XY designed research; MNH, RXB, ML, X-RH, Y-JA, and YG carried out experiments; MNH, RXB, and H-XY analyzed data; MNH, YX, and H-XY wrote the paper. The order of co-authors is measured by contribution.

Corresponding author

Correspondence to Hai-Xin Yuan.

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Competing interests

K-LG is a co-founder of Vivace Therapeutics. YX is a co-founder of Cullgen Inc. X-RH is an employee of Cullgen (Shanghai) Inc. Other authors declare no competing financial interests.

Ethics approval and consent to participate

All animal-related procedures were performed under the Division of Laboratory Animal Medicine Regulations of Fudan University. Written informed consent was obtained from each NSCLC patient who underwent surgery at the Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. This study was approved by the Zhongshan Hospital Research Ethics Committee (No. B2021-131).

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Hu, M., Bao, R., Lin, M. et al. ALK fusion promotes metabolic reprogramming of cancer cells by transcriptionally upregulating PFKFB3. Oncogene 41, 4547–4559 (2022). https://doi.org/10.1038/s41388-022-02453-0

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