Novel application of the published kinase inhibitor set to identify therapeutic targets and pathways in triple negative breast cancer subtypes
Public Deposited- Creator
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Matossian, Margarite D.
- Other Affiliation: Department of Medicine: Section of Hematology and Oncology; Tulane University
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Elliott, Steven
- Other Affiliation: Department of Medicine: Section of Hematology and Oncology; Tulane University
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Hoang, Van T.
- Other Affiliation: Department of Medicine: Section of Hematology and Oncology; Tulane University
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Burks, Hope E.
- Other Affiliation: Department of Medicine: Section of Hematology and Oncology; Tulane University
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Phamduy, Theresa B.
- Other Affiliation: Department of Physics; Tulane University
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Chrisey, Douglas B.
- Other Affiliation: Department of Physics; Tulane University
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Zuercher, William J.
- Affiliation: Eshelman School of Pharmacy
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Drewry, David H.
- Affiliation: Eshelman School of Pharmacy
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Wells, Carrow
- Affiliation: Eshelman School of Pharmacy
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Collins-Burow, Bridgette
- Other Affiliation: Department of Medicine: Section of Hematology and Oncology; Tulane University
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Burow, Matthew E.
- Other Affiliation: Department of Medicine: Section of Hematology and Oncology; Tulane University
- Abstract
- Triple negative breast cancers (TNBCs) have high recurrence and metastasis rates. Acquisition of a mesenchymal morphology and phenotype in addition to driving migration is a consequential process that promotes metastasis. Although some kinases are known to regulate a mesenchymal phenotype, the role for a substantial portion of the human kinome remains uncharacterized. Here we evaluated the Published Kinase Inhibitor Set (PKIS) and screened a panel of TNBC cell lines to evaluate the compounds’ effects on a mesenchymal phenotype. Our screen identified 36 hits representative of twelve kinase inhibitor chemotypes based on reversal of the mesenchymal cell morphology, which was then prioritized to twelve compounds based on gene expression and migratory behavior analyses. We selected the most active compound and confirmed mesenchymal reversal on transcript and protein levels with qRT-PCR and Western Blot. Finally, we utilized a kinase array to identify candidate kinases responsible for the EMT reversal. This investigation shows the novel application to identify previously unrecognized kinase pathways and targets in acquisition of a mesenchymal TNBC phenotype that warrant further investigation. Future studies will examine specific roles of the kinases in mechanisms responsible for acquisition of the mesenchymal and/or migratory phenotype.
- Date of publication
- 2017
- Keyword
- Cancers and Neoplasms
- Enzymology
- Breast Tumors
- Phenotypes
- Developmental Biology
- Genetics
- Molecular Biology Techniques
- Cancer Treatment
- Molecular Biology
- Biotechnology
- Biology and Life Sciences
- Research and Analysis Methods
- Molecular Biology Assays and Analysis Techniques
- Chemistry
- Research Article
- Oncology
- Cell Motility
- Library Screening
- Cell Migration
- Chemical Compounds
- Kinase Inhibitors
- Organic Chemistry
- Breast Cancer
- Physical Sciences
- DOI
- Identifier
- Publisher DOI: https://doi.org/10.1371/journal.pone.0177802
- PMCID: PMC5542472
- Onescience id: 57a1a68dae0948c730f3f33724eef2e789cafc02
- PMID: 28771473
- Resource type
- Article
- Rights statement
- In Copyright
- Journal title
- PloS One
- Journal volume
- 12
- Journal issue
- 8
- Page start
- e0177802
- Language
- English
- ISSN
- 1932-6203
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