Anaplastic lymphoma kinase fusions: Roles in cancer and therapeutic perspectives (Review)

Abstract

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.

A kinome‐wide screen using a NanoLuc LATS luminescent biosensor identifies ALK as a novel regulator of the Hippo pathway in tumorigenesis and immune evasion

“…ALK is an RTK activated by translocation into the locus of other oncogenes, such as ELM4 in breast, lung, and other cancers (19, 21, 39). ALK inhibitors have been clinically used for the treatment of these cancers, including lung cancer (40).…”

Malignant transformation of inflammatory myofibroblastic tumor of urinary bladder: A rare case scenario

“…Most of the IMTs involve clonal rearrangements of ALK gene located on chromosome 2p23 leading to the overexpression of ALK cases and positive cytoplasmic immunostaining for ALK in 50% IMT cases [8]. In addition, several ALK fusion partners have been identified where ALK fusions arise from fusion of the 3' end of the ALK gene (exons 20-29) with the 5' region of a different gene such as TPM3, TPM4, CLTC, RANBP2, CARS, SEC1L1 and ATIC [7,8]. The ALK rearrangement by FISH can substantiate IHC findings although in rare case other none-ALK translocations such as TFG-ROS1 and ETV6-NTRK have also been identified [9].…”

Perinatal complex low‐ and high‐grade glial tumor harboring a novel GIGYF2‐ALK fusion

“…3 ALK protein is highly conserved in humans and has a major role in fetal neural cell development and differentiation. 5 Rearrangements involving ALK were initially identified in anaplastic large B-cell non-Hodgkin lymphomas. ALK-driven tumors share constitutive activation of ALK, leading to cell growth advantage and susceptibility to targeted therapy with several different ALK inhibitors.…”

“…ALK protein is highly conserved in humans and has a major role in fetal neural cell development and differentiation . Rearrangements involving ALK were initially identified in anaplastic large B‐cell non‐Hodgkin lymphomas.…”