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

Chrysostomou, Stelios and Roy, Rajat and Prischi, Filippo and Thamlikitkul, Lucksamon and Chapman, Kathryn L and Mufti, Uwais and Peach, Robert and Ding, Laifeng and Hancock, David and Moore, Christopher and Molina-Arcas, Miriam and Mauri, Francesco and Pinato, David J and Abrahams, Joel M and Ottaviani, Silvia and Castellano, Leandro and Giamas, Georgios and Pascoe, Jennifer and Moonamale, Devmini and Pirrie, Sarah and Gaunt, Claire and Billingham, Lucinda and Steven, Neil M and Cullen, Michael and Hrouda, David and Winkler, Mathias and Post, John and Cohen, Philip and Salpeter, Seth J and Bar, Vered and Zundelevich, Adi and Golan, Shay and Leibovici, Dan and Lara, Romain and Klug, David R and Yaliraki, Sophia N and Barahona, Mauricio and Wang, Yulan and Downward, Julian and Skehel, J Mark and Ali, Maruf MU and Seckl, Michael J and Pardo, Olivier E (2021) 'Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer.' Science Translational Medicine, 13 (602). ISSN 1946-6234

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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 (<jats:italic>P</jats:italic> = 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.

Item Type: Article
Divisions: Faculty of Science and Health > Life Sciences, School of
Depositing User: Elements
Date Deposited: 20 Jul 2021 08:57
Last Modified: 20 Jul 2021 08:57
URI: http://repository.essex.ac.uk/id/eprint/30767

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