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

Mengnan Hu1, Ruoxuan Bao1, Miao Lin2,3

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

Oncogene
|September 5, 2022
PubMed

Insights

Anaplastic lymphoma kinase (ALK) drives cancer by upregulating 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). Targeting PFKFB3 offers a new strategy to overcome ALK tyrosine kinase inhibitor resistance in tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Anaplastic lymphoma kinase (ALK) is a key driver in various cancers, with tyrosine kinase inhibitors (TKIs) being standard treatment.
  • Drug resistance to ALK TKIs remains a significant clinical challenge, necessitating novel therapeutic targets.

Purpose of the Study:

  • To identify novel targets of ALK signaling.
  • To investigate the role of identified targets in ALK-driven cancers and TKI resistance.
  • To explore PFKFB3 as a therapeutic target in ALK-positive tumors.

Main Methods:

  • Quantitative proteomic analysis to identify ALK targets.
  • Assessment of PFKFB3 expression in ALK-positive cancer cells and clinical samples.
  • Investigation of the ALK-STAT3-PFKFB3 signaling axis.
  • Evaluation of PFKFB3 inhibitors in TKI-resistant models.

Main Results:

  • PFKFB3 was identified as a novel ALK target, with its expression dependent on ALK activity in lymphoma and NSCLC.
  • ALK positively regulates PFKFB3 transcription via STAT3, promoting glycolysis and oncogenesis.
  • PFKFB3 inhibition demonstrated efficacy in overcoming TKI resistance in ALK-mutant cells.

Conclusions:

  • A novel ALK-STAT3-PFKFB3 signaling axis promotes cancer cell proliferation and tumorigenesis.
  • PFKFB3 represents a promising therapeutic target for overcoming TKI resistance in ALK-positive cancers.
  • Targeting PFKFB3 offers a potential alternative treatment strategy for ALK-driven malignancies.

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