Format

Send to

Choose Destination
PLoS One. 2017 Aug 3;12(8):e0177802. doi: 10.1371/journal.pone.0177802. eCollection 2017.

Novel application of the published kinase inhibitor set to identify therapeutic targets and pathways in triple negative breast cancer subtypes.

Author information

1
Department of Medicine: Section of Hematology and Oncology, Tulane University, New Orleans, Louisiana, United States of America.
2
Department of Physics, Tulane University, New Orleans, Louisiana, United States of America.
3
Eshelman School of Pharmacy, University of North Carolina - Chapel Hill, Chapel Hill, North Carolina, United States of America.

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.

PMID:
28771473
PMCID:
PMC5542472
DOI:
10.1371/journal.pone.0177802
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center