Receptor Tyrosine Kinase-ALK
The ALK (anaplastic lymphoma kinase) gene encodes a tyrosine kinase belonging to the insulin receptor superfamily. ALK is abundantly expressed in neural tissue during embryogenesis, but levels fall during early evelopment, so that in adults it is expressed only in rare scattered neural cells. ALK was originally identified in anaplastic large cell lymphoma (ALCL) cells as the product of a recurring chromosomal translocation, t (2;5; p23;q35), between the ALK gene on chromosome 2 and the nucleophosmin (NPM) gene on chromosome 5, which gives rise to expression of the NPM–ALK fusion protein. This fusion protein associates with IGF-1R, lead to the up-regulation of the phosphorylation of common downstream targets including STAT3, AKT, and ERK. In ALK-positive NSCLC, ALK gene rearrangement most often involves an inversion within the short arm of chromosome 2 (between loci 2p21 and 2p23), leading to expression of echinoderm microtubule associated protein like 4 (EML4)–ALK, an oncogenic fusion protein composed of the N-terminal portion of EML4 and the entire intracellular portion of ALK. EML4-ALK activates RAS-MAPK (mitogen activated protein kinase) signaling via all 3 major RAS GTPase isoforms (H-, N-, K-RAS) for cell proliferation, acting through the HELP domain of EML4, and JAK/STAT and PI3K/AKT pathways that propagate cell survival.
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References:
Ardini E, Galvani A. ALK Inhibitors, a Pharmaceutical Perspective. Front Oncol. 2012 Feb 22;2:17.
Zhu H, et al. NPM-ALK up-regulates iNOS expression through a STAT3/microRNA-26a-dependent mechanism. J Pathol. 2013 May;230(1):82-94.
Shi B, et al. Molecular and functional characterizations of the association and interactions between nucleophosmin-anaplastic lymphoma kinase and type I insulin-like growth factor receptor. Neoplasia. 2013 Jun;15(6):669-83.
Burns MW, Kim ES. Profile of ceritinib in the treatment of ALK+ metastatic non-small-cell lung cancer. Lung Cancer (Auckl). 2015 May 15;6:35-42.
Hrustanovic G, Bivona TG. RAS-MAPK in ALK targeted therapy resistance. Cell Cycle. 2015;14(23):3661-2.
Koh J, et al. EML4-ALK enhances programmed cell death-ligand 1 expression in pulmonary adenocarcinoma via hypoxia-inducible factor (HIF)-1α and STAT3. Oncoimmunology. 2015 Oct 29;5(3):e1108514. eCollection 2016 Mar.
Rolland DCM, et al. Functional proteogenomics reveals biomarkers and therapeutic targets in lymphomas. Proc Natl Acad Sci U S A. 2017 Jun 20;114(25):6581-6586.
Zhang C, et al. Proteolysis Targeting Chimeras (PROTACs) of Anaplastic Lymphoma Kinase (ALK). Eur J Med Chem. 2018 May 10;151:304-314.
