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Cancer Control Section Heading Section sub The Role of Anaplastic Lymphoma Kinase in Human Cancers Alejandro García-Regalado, PhD 1 and Claudia Haydée González-De la Rosa, PhD 2 1. Postdoctoral Researcher of Natural Sciences Department; 2. Professor and Researcher of Natural Sciences Department, Metropolitan Autonomous University, Mexico City, Mexico Abstract The anaplastic lymphoma kinase (ALK) is a receptor with tyrosine kinase activity, which regulates the development and maintenance of the nervous system. Mutations or amplification in ALK promote tumorogenesis and progression of diverse types of cancer, which makes it an attractive therapeutic target against cancer diseases. Inhibition of its tyrosine kinase activity with small molecules, such as crizotinib, reveals tumor reversion; however, secondary mutations and amplification of the gene mediate resistance to treatment. In this article, we discuss the emerging role of possible therapeutic targets that could overcome the resistance to ALK inhibition in cancer, such as inhibition of other kinases involved in the pathway, inhibition of ALK mutant proteins through the development of new drugs based on its crystallography, and the use of antibodies against ALK. Keywords Cancer, anaplastic lymphoma kinase (ALK), signaling pathway, targeted therapy, acquired drug resistance, combination treatment Disclosure: The authors have no conflicts of interest to declare. Acknowledgements: This work was supported by Consejo Nacional de Ciencia y Tecnología (CONACyT) grants 181534. Alejandro García-Regalado, PhD, acknowledges the support of a postdoctoral fellowship from Universidad Autónoma Metropolitana, Unidad Cuajimalpa (UAM-C). Received: August 19, 2013 Accepted: September 6, 2013 Citation: Oncology & Hematology Review (US), 2013;9(2):149–53 Correspondence: Alejandro García-Regalado, PhD, Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana, Unidad Cuajimalpa, Artificios 40, Col Hidalgo, México, DF, 01120, México. E: alegregalado@yahoo.com.mx Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) belonging to the insulin receptor superfamily. The ALK gene is located on the short arm of chromosome 2 and was first identified as an oncogene activated by chromosomal translocation t(2;5)(p23;q35) in anaplastic large cell lymphoma (ALCL) patients. 1,2 ALK is normally expressed only in the nervous system. Analysis of in situ hybridization of ALK messenger RNA (mRNA) in mice showed that ALK is predominantly expressed in specific regions of the nervous system, such as the thalamus and midbrain, suggesting that ALK plays an important role in the development and maintenance of the central and peripheral nervous systems. 3 Constitutive activation of ALK, derived from chromosomal rearrangements, mutations, or amplification of the ALK gene, has been linked to tumorigenesis and progression of certain cancers such as non-small cell lung carcinoma (NSCLC), breast cancer, and neuroblastoma. 4–7 In this article, we discuss the recent advances in the understanding of resistance to ALK, and possible therapeutic targets that overcome this resistance. Structure of the Anaplastic Lymphoma Kinase Receptor The human ALK gene encodes a 176 kDa protein, which undergoes post- translational modifications, such as N-glycosylation, altering its migration at approximately 220 kDa on SDS/PAGE. 3,8 The ALK receptor is a single- pass transmembrane protein that consists of an extracellular region of 1,030 amino acids (aa), containing an N-terminal signal peptide, two meprin, A-5 protein, receptor protein tyrosine phosphatase mu (MAM) domains separated by a low-density lipoprotein class A (LDL-A) domain, © TO U CH MEDICAL MED IA 2013 and a glycine-rich region proximal to the transmembrane domain that connects the extracellular region with the intracellular region. The MAM domains of this receptor consist of approximately 160 aa, and are thought to participate in cell–cell interactions, 9 whereas the function of the LDL-A domain is still unknown; however, it has been proposed to be involved in ligand recognition. 10 The intracellular region contains a juxtamembrane domain and a tyrosine kinase domain. The juxtamembrane domain function in this receptor is still unknown; however, in other receptors, it functions as a modulator of the kinase catalytic activity. 11 The kinase domain contains three autophosphorylation sites in tyrosine residues 1278, 1282, and 1283, known as the YXXXYY motif, whose phosphorylation regulates the kinase activity of ALK (see Figure 1A). 12,13 Ligands of Anaplastic Lymphoma Kinase Midkine (MK) and pleiotrophin (PTN) are growth factors considered as putative endogenous ALK ligands capable of acting as autocrine/ paracrine signaling molecules. 14,15 MK and PTN are expressed during development of the nervous system and are highly expressed in some cancers where they act as angiogenic factors that drive invasion and metastasis. 16,17 MK is a heparin-binding growth factor with a molecular weight of 13 kDa that regulates development of lung, kidney, bone, and nervous systems. 18 Stoica and co-workers report that MK stimulates ALK phosphorylation and activates phosphatidylinositol 3-kinase (PI3K) and MAP kinase signal transduction. 14 PTN is a 18 kDa protein that acts as a growth factor, regulating neurite outgrowth and proliferation of fibroblasts and endothelial cells. 17 Stoica and co-workers report that PTN binds to the 149