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Oncol Lett. 2019 Feb;17(2):2020-2030. doi: 10.3892/ol.2018.9856. Epub 2018 Dec 20.

Anaplastic lymphoma kinase fusions: Roles in cancer and therapeutic perspectives.

Cao Z1, Gao Q2, Fu M1, Ni N1, Pei Y1, Ou WB1,3.

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Zhejiang Provincial Key Laboratory of Silkworm Bioreactors and Biomedicine, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, P.R. China.
Emergency Department, Tianjin Fourth Central Hospital, Fourth Central Hospital Affiliated with Nankai University, Tianjin 300140, P.R. China.
Zhejiang Provincial Key Laboratory of Applied Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing, Zhejiang 314006, P.R. China.


Receptor tyrosine kinase (RTK) anaplastic lymphoma kinase (ALK) serves a crucial role in brain development. ALK is located on the short arm of chromosome 2 (2p23) and exchange of chromosomal segments with other genes, including nucleophosmin (NPM), echinoderm microtubule-associated protein-like 4 (EML4) and Trk-fused gene (TFG), readily occurs. Such chromosomal translocation results in the formation of chimeric X-ALK fusion oncoproteins, which possess potential oncogenic functions due to constitutive activation of ALK kinase. These proteins contribute to the pathogenesis of various hematological malignancies and solid tumors, including lymphoma, lung cancer, inflammatory myofibroblastic tumors (IMTs), Spitz tumors, renal carcinoma, thyroid cancer, digestive tract cancer, breast cancer, leukemia and ovarian carcinoma. Targeting of ALK fusion oncoproteins exclusively, or in combination with ALK kinase inhibitors including crizotinib, is the most common therapeutic strategy. As is often the case for small-molecule tyrosine kinase inhibitors (TKIs), drug resistance eventually develops via an adaptive secondary mutation in the ALK fusion oncogene, or through engagement of alternative signaling mechanisms. The updated mechanisms of a variety of ALK fusions in tumorigenesis, proliferation and metastasis, in addition to targeted therapies are discussed below.


anaplastic lymphoma kinase; fusion variants; oncogene; resistance mechanisms; targeted therapy

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