Primary Cilia Mediate Diverse Kinase Inhibitor Resistance Mechanisms in Cancer

Andrew D. Jenks, Simon Vyse, Jocelyn P. Wong, Eleftherios Kostaras, Deborah Keller, Thomas Burgoyne, Amelia Shoemark, Athanasios Tsalikis, Maike de la Roche, Martin Michaelis, Jindrich Cinatl, Paul H. Huang, Barbara E. Tanos

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)
12 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)3042-3055
Number of pages14
JournalCell Reports
Volume23
Issue number10
DOIs
Publication statusPublished - 5 Jun 2018

Keywords

  • cilia
  • FGFR
  • Hedgehog pathway
  • kinase inhibitor
  • resistance

Fingerprint

Dive into the research topics of 'Primary Cilia Mediate Diverse Kinase Inhibitor Resistance Mechanisms in Cancer'. Together they form a unique fingerprint.

Cite this