Primary cilia mediate diverse kinase inhibitor resistance mechanisms in cancer

  • Primary cilia are microtubule-based organelles that detect mechanical and chemical stimuli. Although cilia house a number of oncogenic molecules (including Smoothened, KRAS, EGFR, and PDGFR), their precise role in cancer remains unclear. We have interrogated the role of cilia in acquired and de novo resistance to a variety of kinase inhibitors, and found that, in several examples, resistant cells are distinctly characterized by an increase in the number and/or length of cilia with altered structural features. Changes in ciliation seem to be linked to differences in the molecular composition of cilia and result in enhanced Hedgehog pathway activation. Notably, manipulating cilia length via Kif7 knockdown is sufficient to confer drug resistance in drug-sensitive cells. Conversely, targeting of cilia length or integrity through genetic and pharmacological approaches overcomes kinase inhibitor resistance. Our work establishes a role for ciliogenesis and cilia length in promoting cancer drug resistance and has significant translational implications.
Metadaten
Author:Andrew Jenks, Simon Vyse, Jocelyn P. Wong, Eleftherios Kostaras, Deborah Keller, Thomas Burgoyne, Amelia Shoemark, Athanasios Tsalikis, Maike de la Roche, Martin MichaelisORCiDGND, Jindrich Cinatl, Paul H. Huang, Barbara E. Tanos
URN:urn:nbn:de:hebis:30:3-467486
DOI:https://doi.org/10.1016/j.celrep.2018.05.016
ISSN:2211-1247
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/29874589
Parent Title (English):Cell reports
Publisher:Cell Press ; Elsevier
Place of publication:Maryland Heights, MO ; [New York, NY]
Document Type:Article
Language:English
Year of Completion:2018
Date of first Publication:2018/06/05
Publishing Institution:Universit├Ątsbibliothek Johann Christian Senckenberg
Release Date:2018/06/14
Tag:FGFR; Hedgehog pathway; cilia; kinase inhibitor; resistance
Volume:23
Issue:10
Page Number:15
First Page:3042
Last Page:3055
Note:
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
HeBIS-PPN:434237035
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universit├Ątspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0