@article{3687f16f2e3e46349926ac2e31d362e4,
title = "Primary Cilia Mediate Diverse Kinase Inhibitor Resistance Mechanisms in Cancer",
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. Jenks et al. demonstrate that enhanced ciliogenesis can facilitate resistance to a number of kinase inhibitors. Both acquired and de novo resistant cells show increases in cilia numbers and length and increased Hedgehog signaling. Targeting ciliogenesis or ciliary signaling overcomes kinase inhibitor resistance.",
keywords = "cilia, FGFR, Hedgehog pathway, kinase inhibitor, resistance",
author = "Jenks, {Andrew D.} and Simon Vyse and Wong, {Jocelyn P.} and Eleftherios Kostaras and Deborah Keller and Thomas Burgoyne and Amelia Shoemark and Athanasios Tsalikis and {de la Roche}, Maike and Martin Michaelis and Jindrich Cinatl and Huang, {Paul H.} and Tanos, {Barbara E.}",
note = "Funding Information: This research was funded by grants from Sarcoma UK (to B.E.T. [14.2014] and P.H.H. [3.2014]), Kent Cancer Trust (to M.M.), and Hilfe fuer Krebskranke Kinder Frankfurt e.V. and Frankfurter Stiftung fuer Krebskranke Kinder (to J.C.), and CRUK-CI Core Grant ( C14303/A17197 ) and S.H.D. Fellowship ( Wellcome Trust/Royal Society ( 107609) ) (to M.D.R.). We thank Dr. Frank Saran (Neuro-oncology Unit, Royal Marsden Hospital) for additional support. We thank Carsten Janke (Institut Curie) for advice and reagents; Jacek Gaertik (University of Georgia), Kathryn Anderson (MSKCC), Robert Blassberg (CRICK), and Pascal Meier (ICR) for kindly sharing antibodies; Max Liebau (University of Cologne), Stephane Angers (University of Toronto), and Kathryn Anderson (MSKCC) for kindly donating Kif7 expression plasmids. Special thanks to Marc Fivaz (University of Greenwich) for help with MATLAB and Fredrik Wallberg (ICR Imaging core) for general support. We thank Igor Vivanco (ICR), Tony Magee (Imperial College London), and Susana Godinho (Barts Cancer Institute) for critically reading this manuscript. Publisher Copyright: {\textcopyright} 2018 The Authors Copyright: Copyright 2018 Elsevier B.V., All rights reserved.",
year = "2018",
month = jun,
day = "5",
doi = "10.1016/j.celrep.2018.05.016",
language = "English",
volume = "23",
pages = "3042--3055",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Elsevier",
number = "10",
}