A Simple, Highly Visual in Vivo Screen for Anaplastic Lymphoma Kinase Inhibitors
Open accessAbstract
Anaplastic lymphoma kinase (ALK) is an important drug target in many cancers, including lymphoma, neuroblastoma, and lung cancer. Here, we demonstrate proof-of-principle for a novel and inexpensive assay for ALK inhibitor activity and identification in zebrafish. We demonstrate that the human oncogenic ALK fusion, NPM-ALK, drives overproduction of iridophores, a highly visible, shiny pigment cell-type in zebrafish. Treatment with the potent ALK inhibitor, TAE684, fully inhibits production of ALK-dependent iridophores. Using our assay, we test multiple properties of TAE684 in vivo, including efficacy, specificity, and toxicity. We note that TAE684 also inhibits the closely related leukocyte tyrosine kinase (Ltk) that is required for endogenous iridophore development. Similar effects are observed with an independent inhibitor, Crizotinib. Our assay can thus be utilized to identify ALK or LTK inhibitors. Importantly, the natural reflectivity of iridophores lends itself to automation for high throughput assessment of ALK and LTK inhibitor compounds in vivo.
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In shady/ltk mutants, fate specification and proliferation of iridophores, but not other pigment cells, are impeded.
“In shady/ltk mutants fate specification and proliferation of iridophores, but not other pigment cells, are impeded [11, 36].”
From The MITF paralog tfec is required in neural crest development for fate specification of the iridophore lineage from a multipotent pigment cell progenitor (2021) · cites this paper as [36]
The Introduction (page unavailable) says ltk mutants lack iridophores because iridophore fate specification fails. It does not say that proliferation is impeded. The Results and Discussion report no effects on other pigment cells in inhibitor-treated embryos, but do not establish that finding for ltk mutants. (LLM, conf=0.85)
Experimental — accuracy not yet measuredLtk signalling is crucial to fate specification, proliferation and differentiation of iridophores.
“a signalling pathway crucial to fate specification, proliferation and differentiation of iridophores has been highlighted by mutations in the gene encoding the Leukocyte Tyrosine Kinase (Ltk; [11, 36]) receptor tyrosine kinase”
From The MITF paralog tfec is required in neural crest development for fate specification of the iridophore lineage from a multipotent pigment cell progenitor (2021) · cites this paper as [36]
The Introduction says Ltk drives iridophore fate specification, and the Results and Discussion report that activated Ltk rescues iridophore development and produces additional iridophores. Our copy does not establish separate roles for Ltk signalling in iridophore proliferation and differentiation; those parts of the claim go beyond the reported findings. The indexed passages provide section labels but no page numbers. (LLM, conf=0.84)
Experimental — accuracy not yet measuredSox10 and the receptor tyrosine kinase Ltk play crucial roles in iridophore specification.
“In the case of iridophores, as well as Sox10, the receptor tyrosine kinase Leukocyte tyrosine kinase (Ltk) plays a crucial role”
From A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest (2018) · cites this paper as [27]
The Introduction (page unavailable) states that Ltk acts cell-autonomously in zebrafish iridophore fate specification and that ltk mutants lack iridophores. The Results and Discussion and Figure 2 legend (pages unavailable) use a sox10 promoter to drive expression in neural crest cells, but do not establish that Sox10 itself is crucial for iridophore specification. (LLM, conf=0.87)
Experimental — accuracy not yet measuredLoss-of-function ltk mutants lack embryonic and adult iridophores.
“with loss of function mutants lacking embryonic and adult iridophores”
From A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest (2018) · cites this paper as [27]
The Results and Discussion state that embryos with the strongest ltk loss-of-function alleles show no iridophores, while intermediate alleles have reduced numbers. The Introduction likewise describes iridophore loss in developing zebrafish, but our copy does not establish that adult mutants lack iridophores. No page numbers are available in the indexed passages. (LLM, conf=0.88)
Experimental — accuracy not yet measuredConstitutively activated Ltk signalling drives neural crest cells to adopt an iridophore fate.
“constitutively activated Ltk signalling driving NCCs to adopt an iridophore fate [9], [27], [28].”
From A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest (2018) · cites this paper as [27]
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Research works printed but not linked: 2
- [13]13. Galkin, A. V., Melnick, J. S., Kim, S., Hood, T. L., Li, N., Li, L., Xia, G., Steensma, R., Chopiuk, G., Jiang, J., Wan, Y., Ding, P., Liu, Y., Sun, F., Schultz, P. G., Gray, N. S., and Warmuth, M. (2007) Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK, Proc. Natl. Acad. Sci. U. S. A. 104 , 270-275.
- [31]31. Langenau, D. M., Feng, H., Berghmans, S., Kanki, J. P., Kutok, J. L., and Look, A. T. (2005) Cre/lox-regulated transgenic zebrafish model with conditional myc-induced T cell acute lymphoblastic leukemia, Proc. Natl. Acad. Sci. U. S. A. 102 , 6068-6073.
Cited by
Sorted by citations
Petratou, K., Subkhankulova, T., Lister, J. A., Rocco, A., Schwetlick, H., & Kelsh, R. N. (2018) · PLOS Genetics · doi:10.1371/journal.pgen.1007402 · Cited by 69 · see citing works
Self-citationPetratou, K., Spencer, S. A., Kelsh, R. N., & Lister, J. A. (2021) · PLOS ONE · doi:10.1371/journal.pone.0244794 · Cited by 55 · see citing works
Self-citation
- Authors
- Rodrigues, F. S. L. M., Yang, X., Nikaido, M., Liu, Q., & Kelsh, R. N.
- Affiliations
- University of Bath (GB)
- Harvard University (US)
- Corresponding author
- Kelsh, Robert N.
- Venue
- ACS Chemical Biology
- Publisher
- American Chemical Society (ACS)
- Published
- 2012-09-24
- Volume
- 7
- Issue
- 12
- Pages
- 1968-1974
- ISSN
- 1554-8929 (ISSN-L)
- 1554-8937
- OpenAlex
- W2089922936
- Cited by
- 15
- References
- 0
- Citations by year
- 2024: 2 · 2023: 2 · 2021: 2 · 2019: 1 · 2018: 2 · 2017: 1 · 2016: 1 · 2015: 1 · 2014: 1 · 2013: 2
- FWCI
- 0.56
- Type
- journal article
- Language
- en
- Open access
- Licence
- other-oa
- Locations
- ACS Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Pure (University of Bath) (publishedVersion, other-oa)
- The University of Bath Online Publications Store (The University of Bath) (submittedVersion)
- Funders
- Wellcome Trust (077454, 066326)
- Medical Research Council
- Fundação para a Ciência e a Tecnologia
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Zebrafish Biomedical Research Applications
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
- Keywords
- anaplastic lymphoma kinase, ALK inhibitors, NPM-ALK fusion, iridophores, zebrafish, TAE684, crizotinib, high-throughput screening, in vivo assay, drug toxicity, drug specificity
- MeSH terms
- Anaplastic Lymphoma Kinase, Animals, Dose-Response Relationship, Drug, Pyrimidines, Zebrafish, Receptor Protein-Tyrosine Kinases, Protein Kinase Inhibitors
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