Primary Cilia Mediate Diverse Kinase Inhibitor Resistance Mechanisms in Cancer.
Jenks, Andrew D
Wong, Jocelyn P
Huang, Paul H
Tanos, Barbara E
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Jenks, A. D., Vyse, S., Wong, J. P., Kostaras, E., Keller, D., Burgoyne, T., Shoemark, A., et al. (2018). Primary Cilia Mediate Diverse Kinase Inhibitor Resistance Mechanisms in Cancer.. Cell Reports, 23 (10), 3042-3055. https://doi.org/10.1016/j.celrep.2018.05.016
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.
FGFR, Hedgehog pathway, cilia, kinase inhibitor, resistance
This research was partly funded by the Institute of Cancer Research and by grants from Sarcoma UK (to B.E.T. [14.2014] and P.H.H. [3.2014]), Kent Cancer Trust (to M.M.), Hilfe fuer Krebskranke Kinder Frankfurt e.V. and Frankfurter Stiftung fuer Krebskranke Kinder (to J.C.), CRUK-CI Core Grant (C14303/A17197), and S.H.D. Fellowship (Wellcome Trust/Royal Society ) (to M.D.R.). B.E.T. was supported by an ICR fellowship.
WELLCOME TRUST (107609/Z/15/Z)
Cancer Research UK (C14303_do not transfer)
External DOI: https://doi.org/10.1016/j.celrep.2018.05.016
This record's URL: https://www.repository.cam.ac.uk/handle/1810/285895
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/
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