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New perspectives for targeting therapy in ALK-positive human cancers

Oncogene volume 42, pages 1959–1969 (2023)Cite this article

Subjects

Abstract

Anaplastic lymphoma kinase (ALK) is a member of the insulin receptor protein-tyrosine kinase superfamily and was first discovered in anaplastic large-cell lymphoma (ALCL). ALK alterations, including fusions, over-expression and mutations, are highly associated with cancer initiation and progression. This kinase plays an important role in different cancers, from very rare to the more prevalent non-small cell lung cancers. Several ALK inhibitors have been developed and received Food and Drug Administration (FDA) approval. However, like other drugs used in targeted therapies, ALK inhibitors inevitably encounter cancer cell resistance. Therefore, monoclonal antibody screening based on extracellular domain or combination therapies may provide viable alternatives for treating ALK-positive tumors. In this review, we discuss the current understanding of wild-type ALK and fusion protein structures, the pathological functions of ALK, ALK target therapy, drug resistance and future therapeutic directions.

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Fig. 1: The structure of ALK.
Fig. 2: Schematic model of inactive ALK and ligand-active ALK.
Fig. 3: Body diagram of all tumors currently linked to ALK-fusion proteins.
Fig. 4: Signaling pathways of ALK.
Fig. 5: Development of ALK inhibitors.

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Acknowledgements

The authors thank Kyle Laster for checking the grammatical mistakes.

Funding

This study was supported by the National Natural Science Foundation of China (No. 82073075, 81872335, 82203290); the Science and Technology Project of Henan Province (No. 212102310880, 22102310416); and Henan provincial Medical Science and Technology Research Project (No. SBGJ202102071).

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Authors and Affiliations

  1. Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, PR China

    Simin Zhao, Qingxin Xia & Zigang Dong

  2. China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, PR China

    Simin Zhao, Jian Li, Kangdong Liu & Zigang Dong

  3. Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, Henan, PR China

    Kangdong Liu & Zigang Dong

  4. Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan, PR China

    Kangdong Liu & Zigang Dong

Authors
  1. Simin Zhao
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  2. Jian Li
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  3. Qingxin Xia
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  4. Kangdong Liu
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  5. Zigang Dong
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Contributions

All authors made substantial, direct and intellectual contribution to the review. ZD: Conceptualization, Supervision; SZ: Conceptualization, Data curation, Writing - Original Draft; JL: Validation, Software; QX: Visualization, Investigation; KL: Writing- Reviewing and Editing.

Corresponding authors

Correspondence to Qingxin Xia, Kangdong Liu or Zigang Dong.

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The authors declare no competing interests.

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Zhao, S., Li, J., Xia, Q. et al. New perspectives for targeting therapy in ALK-positive human cancers. Oncogene 42, 1959–1969 (2023). https://doi.org/10.1038/s41388-023-02712-8

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