Jenks, Andrew D and Vyse, Simon and Wong, Jocelyn P and Kostaras, Eleftherios and Keller, Deborah and Burgoyne, Thomas and Shoemark, Amelia and Tsalikis, Athanasios and de la Roche, Maike and Michaelis, Martin and Cinatl, Jindrich and Huang, Paul H and Tanos, Barbara E (2018) Primary Cilia Mediate Diverse Kinase Inhibitor Resistance Mechanisms in Cancer. Cell reports, 23 (10). pp. 3042-3055.
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.
RM Therapeutics. Pharmacology
University of Kent