Signaling by ALK in cancer

Stable Identifier
Homo sapiens
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Anaplastic lymphoma kinase (ALK) was first identified in the context of an oncogenic fusion with nucleophosmin (NPM) in anaplastic large cell lymphoma (ALCL) (Morris et al, 1994). NPM-ALK fusions occur in approximately 75-80% of ALCL cases and at lower frequencies in other cancers, including non-small cell lung cancer, neuroblastoma and inflammatory myofibroblastic tumors (IFTs) (Morris et al, 1994; Shiota et al, 1994; reviewed in Della Corte et al, 2018; Werner et al, 2017).

In addition to NPM, fusions of ALK with nearly 30 other 5' partners have since been identified, although these tend to occur at lower frequencies in the cancers in which they appear (reviewed in Chiarle et al, 2008; Della Corte et al, 2018; Roskoski, 2013; Hallberg and Palmer, 2016). In general, ALK fusions combine the 5' end of the partner gene which contributes a dimerization domain with the intracellular portion of the ALK receptor including the kinase domain, and lead to constitutive signaling by virtue of the partner-domain mediated dimerization (reviewed in Roskoski, 2013; Della Corte et al, 2018).

In addition to translocation events that lead to fusion proteins, the ALK gene also contributes to oncogenesis as a result of gene amplification and overexpression events, as well as being subject to activating missense mutations (reviewed in Della Corte et al, 2018; Hallberg and Palmer, 2016).

Oncogenic ALK activity can be targeted with tyrosine kinase inhibitors, although resistance often arises due to secondary mutations or activation of bypass pathways (reviewed in Roskoski, 2013; Della Corte et al, 2018; Hallberg and Palmer, 2016; Werner et al, 2017; Lovly and Pao, 2012).
Literature References
PubMed ID Title Journal Year
27879258 Nucleophosmin-anaplastic lymphoma kinase: the ultimate oncogene and therapeutic target

Zhao, C, Wasik, MA, Zhang, Q, Werner, MT

Blood 2017
29455642 Role and targeting of anaplastic lymphoma kinase in cancer

Troiani, T, Viscardi, G, Morgillo, F, Fasano, M, Martinelli, E, Ciardiello, F, Della Corte, CM, Di Liello, R

Mol. Cancer 2018
18097461 The anaplastic lymphoma kinase in the pathogenesis of cancer

Chiarle, R, Piva, R, Ambrogio, C, Inghirami, G, Voena, C

Nat. Rev. Cancer 2008
7824924 Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma

Morris, SW, Shapiro, DN, Kirstein, MN, Saltman, DL, Look, AT, Valentine, MB, Dittmer, K

Science 1995
23201355 Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and pharmacological inhibition

Roskoski, R

Pharmacol. Res. 2013
8183550 Hyperphosphorylation of a novel 80 kDa protein-tyrosine kinase similar to Ltk in a human Ki-1 lymphoma cell line, AMS3

Yamamoto, T, Semba, T, Satoh, H, Fujimoto, J, Mori, S, Shiota, M

Oncogene 1994
24060861 Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology

Palmer, RH, Hallberg, B

Nat. Rev. Cancer 2013
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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