scholarly journals Evolutionary analyses guide selection of model systems to investigate proto-oncogene function in ALK and LTK

2019 ◽  
Author(s):  
Zheng Wang ◽  
Alex Dornburg ◽  
Junrui Wang ◽  
Elizabeth S. Mo ◽  
Francesc Lopez-Giraldez ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Anaplastic Lymphoma Kinase ◽  
Model Systems ◽  
Model Organisms ◽  
Tyrosine Kinase Receptors ◽  
Evolutionary Analysis ◽  
Anaplastic Lymphoma ◽  
Evolutionary Innovation ◽  
Therapeutic Development ◽  
Selection Of

AbstractModel systems to investigate oncogene-driven cancer have played an essential role in the development of therapies for cancer. However, not all systems are appropriate for all therapeutic targets. Knowing where and when proto-oncogenes and their interactors originated in evolutionary history is key to understanding which organisms can serve as models. Here we investigate two tyrosine kinase receptors that underlie tumorigenesis in cancer: anaplastic lymphoma kinase (ALK) and leukocyte tyrosine kinase (LTK). In Drosophila melanogaster, Caenorhabitis elegans, and Homo sapiens, the discovery of putative ligands Jeb, Hen-1, and AUG has the potential to accelerate the development of novel therapeutics. However, homology of these ligands and receptors is unclear. We performed an exhaustive search for their homologs spanning the metazoan tree of life. Jeb and Hen-1 were restricted to species that diverged prior to the origin of all vertebrates. No non-vertebrate species had ligands orthologous to AUG. Instead, an ancestral receptor tyrosine kinase and AUG gene were present in early vertebrates and are still solitary in lamprey; we demonstrate that the early embryonic expression of AUG in lamprey parallels its expression in model mammal systems. The presence of ALK and LTK in jawed vertebrates is an evolutionary innovation, as is a previously unrecognized functional convergence within ALK and LTK occurring between actinopterygians and sarcopterygians. Our results provide the phylogenetic context necessary for the selection of model organisms that will provide informative investigations of the biology of these critically important tyrosine kinase receptors, enabling successful therapeutic development.SignificanceThe anaplastic lymphoma kinase ALK can be oncogenically altered to become a driver of several malignancies, including non-small-cell lung cancer and anaplastic large-cell lymphomas. The development of therapeutics targeting this gene depend on the discovery of its interacting partner ligands in relevant model organisms. ALK is found across most major animal groups including mammals, fishes, and invertebrates. Correspondly, several candidate ligands for ALK and its duplicate LTK have been advanced by research in model species. However their homology to the human ligands and therefore their potential to guide therapeutic development is unknown. Our comparative evolutionary analysis revealed which model organisms had functional receptor-ligand pairings that are informative regarding the role of these genes in human tumorigenesis.

Targeting Small Molecule Tyrosine Kinases by Polyphenols: New Move Towards Anti-tumor Drug Discovery

2020 ◽  
Vol 17 (5) ◽  
pp. 585-615 ◽  
Author(s):  
Nikhil S. Sakle ◽  
Shweta A. More ◽  
Sachin A. Dhawale ◽  
Santosh N. Mokale
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Small Molecule ◽  
Anaplastic Lymphoma Kinase ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Myelogenous Leukemia ◽  
Cell Functions ◽  
Anaplastic Lymphoma

Background: Cancer is a complex disease involving genetic and epigenetic alteration that allows cells to escape normal homeostasis. Kinases play a crucial role in signaling pathways that regulate cell functions. Deregulation of kinases leads to a variety of pathological changes, activating cancer cell proliferation and metastases. The molecular mechanism of cancer is complex and the dysregulation of tyrosine kinases like Anaplastic Lymphoma Kinase (ALK), Bcr-Abl (Fusion gene found in patient with Chronic Myelogenous Leukemia (CML), JAK (Janus Activated Kinase), Src Family Kinases (SFKs), ALK (Anaplastic lymphoma Kinase), c-MET (Mesenchymal- Epithelial Transition), EGFR (Epidermal Growth Factor receptor), PDGFR (Platelet-Derived Growth Factor Receptor), RET (Rearranged during Transfection) and VEGFR (Vascular Endothelial Growth Factor Receptor) plays major role in the process of carcinogenesis. Recently, kinase inhibitors have overcome many problems of traditional cancer chemotherapy as they effectively separate out normal, non-cancer cells as well as rapidly multiplying cancer cells. Methods: Electronic databases were searched to explore the small molecule tyrosine kinases by polyphenols with the help of docking study (Glide-7.6 program interfaced with Maestro-v11.3 of Schrödinger 2017) to show the binding energies of polyphenols inhibitor with different tyrosine kinases in order to differentiate between the targets. Results: From the literature survey, it was observed that the number of polyphenols derived from natural sources alters the expression and signaling cascade of tyrosine kinase in various tumor models. Therefore, the development of polyphenols as a tyrosine kinase inhibitor against targeted proteins is regarded as an upcoming trend for chemoprevention. Conclusion: In this review, we have discussed the role of polyphenols as chemoreceptive which will help in future for the development and discovery of novel semisynthetic anticancer agents coupled with polyphenols.

scholarly journals 4558 Investigating the functional consequences of anaplastic lymphoma kinase (ALK) mutations arising upon Lorlatinib treatment

2020 ◽  
Vol 4 (s1) ◽  
pp. 9-10
Author(s):  
Gabriela Maria Witek ◽  
Whelton Miller ◽  
David Slochower ◽  
Esther Berko ◽  
Yael Mossé ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Anaplastic Lymphoma Kinase ◽  
De Novo ◽  
Point Mutations ◽  
Md Simulations ◽  
Competitive Inhibitor ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Anaplastic Lymphoma ◽  
Mechanism Of Resistance

OBJECTIVES/GOALS: Neuroblastoma (NB) is an embryonal cancer of the sympathetic nervous system that affects mostly infants and young children. The complex genetic background present across NB patients results in diverse clinical response and difficulty in individualizing therapy. Currently, NB patients undergo a regimen of genotoxic chemotherapeutics, radiation therapy, and new immunotherapy that, while effective, has significant side effects, including excruciating pain. One promising avenue for targeted therapy in neuroblastoma focuses on anaplastic lymphoma kinase (ALK), a cell surface neural receptor tyrosine kinase. We previously identified activating point mutations within the tyrosine kinase domain of ALK as the primary cause of hereditary NB, and we and others subsequently showed that these same alterations are the most common somatic single-nucleotide mutations in the sporadic forms of the disease. Crizotinib, a first-generation small molecule ATP-competitive inhibitor of the ALK tyrosine kinase, showed limited anti-tumor activity in patients with relapsed NB harboring ALK F1174 and F1245 mutations. We have demonstrated that lorlatinib, a novel ATP-competitive ALK inhibitor, overcomes this de novo resistance in preclinical models of ALK-driven NB. Recent clinical trials with lorlatinib in patients with non-small cell lung cancer harboring an ALK fusion, and in patients with NB harboring ALK mutations show the emergence of multiple or compound ALK mutations as a mechanism of resistance. We postulate that these compound mutations disrupt the interaction between and ALK and cause resistance. In this study, we employ a computational approach to model mutated ALK in complex with lorlatinib as well as ATP to understand whether the new mutations alter the affinity or mode of lorlatinib/ATP binding to ALK, and thus cause suboptimal ALK inhibition. METHODS/STUDY POPULATION: We employ methods in computational structural biology and drug design, primarily based on molecular modeling, molecular dynamics (MD), and molecular docking. Based on existing crystal structures of wildtype ALK, we model the mutations and perform MD simulations in order to characterize the activation state of the protein as well as perform ensemble docking calculations to assess the binding affinities and modes in ALK-lorlatinib and ALK-ATP complexes. RESULTS/ANTICIPATED RESULTS: We expect that the compound mutations cause resistance to lorlatinib either by lowering protein affinity for the drug or increasing the affinity for ATP. Alternatively, the compound mutations may disrupt the protein activation state, in which case ALK may no longer be active, and another protein/pathway could be driving the resistance. DISCUSSION/SIGNIFICANCE OF IMPACT: The results of this study will enable the understanding of the mechanism of resistance to lorlatinib and facilitate the design of new ALK inhibitors, or help develop more optimal and mechanism-guided therapies aimed to overcome the resistance.

scholarly journals p130Cas mediates the transforming properties of the anaplastic lymphoma kinase

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3907-3916 ◽  
Author(s):  
Chiara Ambrogio ◽  
Claudia Voena ◽  
Andrea D. Manazza ◽  
Roberto Piva ◽  
Ludovica Riera ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Anaplastic Lymphoma Kinase ◽  
Kinase Activity ◽  
Adaptor Protein ◽  
Dominant Negative ◽  
Lymphoid Cells ◽  
Src Tyrosine Kinase ◽  
Anaplastic Lymphoma ◽  
Proteomic Approach

Translocations of the anaplastic lymphoma kinase (ALK) gene have been described in anaplastic large-cell lymphomas (ALCLs) and in stromal tumors. The most frequent translocation, t(2;5), generates the fusion protein nucleophosmin (NPM)–ALK with intrinsic tyrosine kinase activity. Along with transformation, NPM-ALK induces morphologic changes in fibroblasts and lymphoid cells, suggesting a direct role of ALK in cell shaping. In this study, we used a mass-spectrometry–based proteomic approach to search for proteins involved in cytoskeleton remodeling and identified p130Cas (p130 Crk-associated substrate) as a novel interactor of NPM-ALK. In 293 cells and in fibroblasts as well as in human ALK-positive lymphoma cell lines, NPM-ALK was able to bind p130Cas and to induce its phosphorylation. Both of the effects were dependent on ALK kinase activity and on the adaptor protein growth factor receptor–bound protein 2 (Grb2), since no binding or phosphorylation was found with the kinase-dead mutant NPM-ALKK210R or in the presence of a Grb2 dominant-negative protein. Phosphorylation of p130Cas by NPM-ALK was partially independent from Src (tyrosine kinase pp60c-src) kinase activity, as it was still detectable in Syf-/- cells. Finally, p130Cas-/- (also known as Bcar1-/-) fibroblasts expressing NPM-ALK showed impaired actin filament depolymerization and were no longer transformed compared with wild-type cells, indicating an essential role of p130Cas activation in ALK-mediated transformation.

scholarly journals Activation and Inhibition of Anaplastic Lymphoma Kinase Receptor Tyrosine Kinase by Monoclonal Antibodies and Absence of Agonist Activity of Pleiotrophin

2005 ◽  
Vol 280 (28) ◽  
pp. 26039-26048 ◽  
Author(s):  
Christel Moog-Lutz ◽  
Joffrey Degoutin ◽  
Jean Y. Gouzi ◽  
Yvelyne Frobert ◽  
Nicole Brunet-de Carvalho ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Anaplastic Lymphoma Kinase ◽  
Agonist Activity ◽  
Anaplastic Lymphoma

The Role of Anaplastic Lymphoma Kinase in Human Cancers

2013 ◽  
Vol 09 (02) ◽  
pp. 149 ◽  
Author(s):  
Alejandro García-Regalado ◽  
Claudia Haydée González-De la Rosa ◽  
◽  
Keyword(s):  
Tyrosine Kinase ◽  
Anaplastic Lymphoma Kinase ◽  
Kinase Activity ◽  
New Drugs ◽  
Tyrosine Kinase Activity ◽  
Mutant Proteins ◽  
Anaplastic Lymphoma ◽  
Attractive Therapeutic Target ◽  
Pathway Inhibition

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.

scholarly journals A crucial role for the Anaplastic lymphoma kinase receptor tyrosine kinase in gut development in Drosophila melanogaster

EMBO Reports ◽  
2003 ◽  
Vol 4 (8) ◽  
pp. 781-786 ◽  
Author(s):  
Christina E Lorén ◽  
Camilla Englund ◽  
Caroline Grabbe ◽  
Bengt Hallberg ◽  
Tony Hunter ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Anaplastic Lymphoma Kinase ◽  
Crucial Role ◽  
Gut Development ◽  
Anaplastic Lymphoma
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