TY  - JOUR
A1  - Jenks, Andrew
A1  - Vyse, Simon
A1  - Wong, Jocelyn P.
A1  - Kostaras, Eleftherios
A1  - Keller, Deborah
A1  - Burgoyne, Thomas
A1  - Shoemark, Amelia
A1  - Tsalikis, Athanasios
A1  - Roche, Maike de la
A1  - Michaelis, Martin
A1  - Cinatl, Jindrich
A1  - Huang, Paul H.
A1  - Tanos, Barbara E.
T1  - Primary cilia mediate diverse kinase inhibitor resistance mechanisms in cancer
T2  - Cell reports
N2  - 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.
KW  - FGFR
KW  - Hedgehog pathway
KW  - cilia
KW  - kinase inhibitor
KW  - resistance
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/46748
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-467486
SN  - 2211-1247
N1  - This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
VL  - 23
IS  - 10
SP  - 3042
EP  - 3055
PB  - Cell Press ; Elsevier
CY  - Maryland Heights, MO ; [New York, NY]
ER  -