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Primary Cilia Mediate Diverse Kinase Inhibitor Resistance Mechanisms in Cancer.

Jenks, Andrew D, Vyse, Simon, Wong, Jocelyn P, Kostaras, Eleftherios, Keller, Deborah, Burgoyne, Thomas, Shoemark, Amelia, Tsalikis, Athanasios, de la Roche, Maike, Michaelis, Martin, and others. (2018) Primary Cilia Mediate Diverse Kinase Inhibitor Resistance Mechanisms in Cancer. Cell reports, 23 (10). pp. 3042-3055. ISSN 2211-1247. (doi:10.1016/j.celrep.2018.05.016)

Abstract

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.

Item Type: Article
DOI/Identification number: 10.1016/j.celrep.2018.05.016
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Martin Michaelis
Date Deposited: 08 Jun 2018 09:20 UTC
Last Modified: 29 May 2019 20:36 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/67237 (The current URI for this page, for reference purposes)
Michaelis, Martin: https://orcid.org/0000-0002-5710-5888
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