Adopting ALK and LTK

Lemke, Greg

doi:10.1073/pnas.1521923113

Cited by 10 publications

(7 citation statements)

References 16 publications

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“…Somewhat different models are those of Elf et al [34] and Deris et al [35], who consider bistabilities of cells resulting either from membrane properties or drug resistance. Other models focus on mechanisms of microscopic control of ribosome synthesis, such as the "stringent response", a negative feedback mechanism triggered when some of cell's excess usable energetic molecules are converted to unusable ppGpp as response to endogenous limitations of aminoacids [21,28,36]. Because of its simplicity, the present treatment could be extended to explore other factors that are of interest, such as cellular geometry (surface-volume considerations), multi-drug effects [37], or drug-dependent cellular multistabilities that lead to antibiotic resistance and persistence [34,35].…”

Section: Discussionmentioning

confidence: 99%

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Modeling the overproduction of ribosomes when antibacterial drugs act on cells

Maitra

Dill

2015

Preprint

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Bacteria that are subjected to ribosome-inhibiting antibiotic drugs show an interesting behavior: Although the drug slows down cell growth, it also paradoxically increases the cell's concentration of ribosomes. We combine our earlier nonlinear model of the energy-biomass balance in undrugged Escherichia coli cells with Michaelis-Menten binding of drugs that inactivate ribosomes. Predictions are in good agreement with experiments on ribosomal concentrations and synthesis rates versus drug concentrations and growth rates. The model indicates that the added drug drives the cell to overproduce ribosomes, keeping roughly constant the level of ribosomes producing ribosomal proteins, an important quantity for cell growth. The model also predicts that ribosomal production rates should increase and then decrease with added drug. This model gives insights into the driving forces in cells and suggests new experiments.

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Section: Discussionmentioning

confidence: 99%

“…The functional forms in Eqs. (5), (6), (7) reflect wildtype regulatory mechanisms that coordinate the syntheses of ribosomal and non-ribosomal proteins, which are complex [27,28] and depend on the cell's energy status. To capture these dependencies, we adopt the undrugged cell functions [18]:…”

Section: A Minimal Model Of E Coli In the Presence Of Drugsmentioning

confidence: 99%

Modeling the overproduction of ribosomes when antibacterial drugs act on cells

Maitra

Dill

2015

Preprint

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“…Activation of endogenous ALK requires ligand-dependent receptor dimerization and autophosphorylation. Recent work has established Augmentor α and β (FAM150) as the ligand for ALK (10–12). Although little is known about the biological function of ALK in humans, insights may be gleaned from studying model systems.…”

Section: Alk Biologymentioning

confidence: 99%

Targeting ALK: Precision Medicine Takes on Drug Resistance

2017

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Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, including non-small-cell lung cancer (NSCLC). However, the clinical benefit of targeting ALK using tyrosine kinase inhibitors (TKIs) is almost universally limited by the emergence of drug resistance. Diverse mechanisms of resistance to ALK TKIs have now been discovered, and these basic mechanisms are informing the development of novel therapeutic strategies to overcome resistance in the clinic. In this Review, we summarize the current successes and challenges of targeting ALK.

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“…Justified by structural conservation of ALK between invertebrate models as diverse as fruit flies, nematodes, and humans, model organisms have been central to illuminating the biology related to these oncogenic alterations. However, translation of fundamental findings in model organisms (12,(29)(30)(31) to targeted therapeutic development in humans necessitates disentangling potentially complex patterns of divergent and convergent evolution.…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Dornburg

Wang³

et al. 2019

Preprint

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Model 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.

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Adopting ALK and LTK

Cited by 10 publications

References 16 publications

Modeling the overproduction of ribosomes when antibacterial drugs act on cells

Modeling the overproduction of ribosomes when antibacterial drugs act on cells

Targeting ALK: Precision Medicine Takes on Drug Resistance

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

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