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Primary Cilia Mediate Diverse Kinase Inhibitor Resistance Mechanisms in Cancer

Jenks, AD; Vyse, S; Wong, JP; Kostaras, E; Keller, D; Burgoyne, T; Shoemark, A; ... Tanos, BE; + view all (2018) Primary Cilia Mediate Diverse Kinase Inhibitor Resistance Mechanisms in Cancer. Cell Reports , 23 (10) pp. 3042-3055. 10.1016/j.celrep.2018.05.016. Green open access

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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.

Type: Article
Title: Primary Cilia Mediate Diverse Kinase Inhibitor Resistance Mechanisms in Cancer
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.celrep.2018.05.016
Publisher version: https://doi.org/10.1016/j.celrep.2018.05.016
Language: English
Additional information: © 2018 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Keywords: Science & Technology, Life Sciences & Biomedicine, Cell Biology, Cell Lung-Cancer, Human Glioblastoma, Drug-Resistance, Hedgehog, Transcription, Ciliogenesis, Transport, Elegans, Tumors, Alpha
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10053251
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