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Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer

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Title: Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer
Authors: Pardo, O
Chrysostomou, S
Roy, R
Prischi, F
Thamlikitkul, L
Chapman, KL
Mufti, U
Peach, R
Ding, L
Hancock, D
Moore, C
Molina-Arcas, M
Mauri, F
Pinato, DJ
Abrahams, JM
Ottaviani, S
Castellano, L
Giamas, G
Pascoe, J
Moonamale, D
Pirrie, S
Gaunt, C
Billingham, L
Steven, NM
Cullen, M
Hrouda, D
Winkler, M
Post, J
Cohen, P
Salpeter, SJ
Bar, V
Zundelevich, A
Golan, S
Leibovici, D
Lara, R
Klug, DR
Yaliraki, SN
Barahona, M
Wang, Y
Downward, J
Skehel, JM
Ali, MMU
Seckl, MJ
Item Type: Journal Article
Abstract: Lung and bladder cancers are mostly incurable because of the early development of drug resistance and metastatic dissemination. Hence, improved therapies that tackle these two processes are urgently needed to improve clinical outcome. We have identified RSK4 as a promoter of drug resistance and metastasis in lung and bladder cancer cells. Silencing this kinase, through either RNA interference or CRISPR, sensitized tumor cells to chemotherapy and hindered metastasis in vitro and in vivo in a tail vein injection model. Drug screening revealed several floxacin antibiotics as potent RSK4 activation inhibitors, and trovafloxacin reproduced all effects of RSK4 silencing in vitro and in/ex vivo using lung cancer xenograft and genetically engineered mouse models and bladder tumor explants. Through x-ray structure determination and Markov transient and Deuterium exchange analyses, we identified the allosteric binding site and revealed how this compound blocks RSK4 kinase activation through binding to an allosteric site and mimicking a kinase autoinhibitory mechanism involving the RSK4’s hydrophobic motif. Last, we show that patients undergoing chemotherapy and adhering to prophylactic levofloxacin in the large placebo-controlled randomized phase 3 SIGNIFICANT trial had significantly increased (P = 0.048) long-term overall survival times. Hence, we suggest that RSK4 inhibition may represent an effective therapeutic strategy for treating lung and bladder cancer.
Issue Date: 14-Jul-2021
Date of Acceptance: 9-Jun-2021
URI: http://hdl.handle.net/10044/1/90380
DOI: 10.1126/scitranslmed.aba4627
ISSN: 1946-6234
Publisher: American Association for the Advancement of Science
Journal / Book Title: Science Translational Medicine
Volume: 13
Issue: 602
Copyright Statement: © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works https://www.sciencemag.org/about/science-licenses-journal-article-reuseThis is an article distributed under the terms of the Science Journals Default License.
Sponsor/Funder: Cancer Treatment & Research Trust
Cancer Treatment & Research Trust
IP2IPO Innovations Limited
Cancer Research UK
Cancer Research UK
Engineering & Physical Science Research Council (EPSRC)
Engineering and Physical Sciences Research Council
Funder's Grant Number: n/a
n/a
6037
A20886
EP/N014529/1
EP/L015498/1
Keywords: 06 Biological Sciences
11 Medical and Health Sciences
Publication Status: Published
Article Number: ARTN eaba4627
Appears in Collections:Department of Surgery and Cancer
Mathematics
Chemistry
Biological and Biophysical Chemistry
Applied Mathematics and Mathematical Physics
Faculty of Natural Sciences