Changes in cell morphology guide identification of tubulin as the off-target for protein kinase inhibitors. (August 2018)

• Record Type: Journal Article
• Authors: Hoque, Monira; Abbassi, Ramzi H.; Froio, Danielle; Man, Jennifer; Johns, Terrance G.; Stringer, Brett W.; Day, Bryan W.; Pajic, Marina; Kassiou, Michael; Munoz, Lenka
• Is Part Of: Pharmacological research. Volume 134(2018)
• Page Start: 166
• Page End: 178
• Publication Date: 2018-08
• Subjects: ALK anaplastic lymphoma kinase -- ATP adenosine triphosphate -- BCR-ABL Breakpoint cluster region–Abelson -- DMEM Dulbecco Modified Eagle Medium -- EGFR epidermal growth factor receptor -- FUCCI Fluorescence Ubiquitination Cell Cycle Indicator -- HER human epidermal growth factor receptor -- MET receptor tyrosine kinase Met -- MERTK Mer tyrosine kinase -- PLK4 Polo-like kinase 4; Kinase inhibitors -- Microtubule-targeting agents -- Off-targets -- Cell morphology -- Glioblastoma; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2018.06.023
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: In the field of kinase inhibitors for applications in cancer research, tubulin is emerging as a targeted cellular protein that can significantly contribute to their activities. However, investigation of kinase inhibitors beyond the kinome is an area often neglected. Herein, we describe the results of pharmacological studies using drugs targeting kinases, tubulin or both. A key finding is that if cells are treated with a kinase inhibitor unintentionally targeting tubulin, their characteristic shape will diminish within a short timeframe. These changes in cell morphology are not seen when cells are treated with bona fide kinase inhibitors that do not directly target tubulin. Thus, early changes in cell morphology upon treatments are a strong indication that the inhibitor is directly targeting tubulin. Recognizing tubulin as a target of kinase inhibitors will build confidence in the future mechanistic studies using kinase inhibitors.