2. Academic Validation
  3. ALK fusion promotes metabolic reprogramming of cancer cells by transcriptionally upregulating PFKFB3

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

  • Oncogene. 2022 Sep;41(40):4547-4559. doi: 10.1038/s41388-022-02453-0.
Mengnan Hu  # 1,  Ruoxuan Bao  # 1,  Miao Lin  # 2 3,  Xiao-Ran Han 4,  Ying-Jie Ai 5,  Yun Gao 1,  Kun-Liang Guan 6,  Yue Xiong 7,  Hai-Xin Yuan 8 9
Affiliations

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.
  • 2 Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 3 Department of Thoracic Surgery, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China.
  • 4 Cullgen (Shanghai) Inc., 230 Chuan Hong Road, Pu Dong New Area, Shanghai, China.
  • 5 Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 6 Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, 92093, USA.
  • 7 Cullgen Inc., 12671 High Bluff Drive, San Diego, CA, 92130, USA.
  • 8 The Fifth People's Hospital of Shanghai and the Molecular and Cell Biology Laboratory of the Institutes of Biomedical Sciences, Fudan University, Shanghai, China. yuanhaixin@fudan.edu.cn.
  • 9 Center for Novel Target and Therapeutic Intervention, Chongqing Medical University, Chongqing, China. yuanhaixin@fudan.edu.cn.
  • # Contributed equally.
PMID: 36064579 DOI: 10.1038/s41388-022-02453-0
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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