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

Issued Date

2021-07-14

Resource Type

Article

ISSN

19466242
19466234

DOI

10.1126/SCITRANSLMED.ABA4627

Other identifier(s)

2-s2.0-85111713891

Rights

Mahidol University

Rights Holder(s)

SCOPUS

Bibliographic Citation

Science Translational Medicine. Vol.13, No.602 (2021)

Suggested Citation

Stelios Chrysostomou, Rajat Roy, Filippo Prischi, Lucksamon Thamlikitkul, Kathryn L. Chapman, Uwais Mufti, Robert Peach, Laifeng Ding, David Hancock, Christopher Moore, Miriam Molina-Arcas, Francesco Mauri, David J. Pinato, Joel M. Abrahams, Silvia Ottaviani, Leandro Castellano, Georgios Giamas, Jennifer Pascoe, Devmini Moonamale, Sarah Pirrie, Claire Gaunt, Lucinda Billingham, Neil M. Steven, Michael Cullen, David Hrouda, Mathias Winkler, John Post, Philip Cohen, Seth J. Salpeter, Vered Bar, Adi Zundelevich, Shay Golan, Dan Leibovici, Romain Lara, David R. Klug, Sophia N. Yaliraki, Mauricio Barahona, Yulan Wang, Julian Downward, J. Mark Skehel, Maruf M.U. Ali, Michael J. Seckl, Olivier E. Pardo Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer. Science Translational Medicine. Vol.13, No.602 (2021). doi:10.1126/SCITRANSLMED.ABA4627 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/78032

Research Projects

Organizational Units

Authors

Journal Issue

Thesis

Title

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

Author(s)

Stelios Chrysostomou
 Rajat Roy
 Filippo Prischi
 Lucksamon Thamlikitkul
 Kathryn L. Chapman
 Uwais Mufti
 Robert Peach
 Laifeng Ding
 David Hancock
 Christopher Moore
 Miriam Molina-Arcas
 Francesco Mauri
 David J. Pinato
 Joel M. Abrahams
 Silvia Ottaviani
 Leandro Castellano
 Georgios Giamas
 Jennifer Pascoe
 Devmini Moonamale
 Sarah Pirrie
 Claire Gaunt
 Lucinda Billingham
 Neil M. Steven
 Michael Cullen
 David Hrouda
 Mathias Winkler
 John Post
 Philip Cohen
 Seth J. Salpeter
 Vered Bar
 Adi Zundelevich
 Shay Golan
 Dan Leibovici
 Romain Lara
 David R. Klug
 Sophia N. Yaliraki
 Mauricio Barahona
 Yulan Wang
 Julian Downward
 J. Mark Skehel
 Maruf M.U. Ali
 Michael J. Seckl
 Olivier E. Pardo

Other Contributor(s)

Siriraj Hospital
 Domainex Ltd.
 The Francis Crick Institute
 Kaplan Medical Center
 Universitätsklinikum Würzburg
 University Hospitals Birmingham NHS Foundation Trust
 Rabin Medical Center Israel
 Wuhan Institute of Physics and Mathematics Chinese Academy of Sciences
 University of Birmingham
 University of Sussex
 Medical Research Council
 Imperial College London
 Charing Cross Hospital
 University of Dundee
 Nanyang Technological University
 AstraZeneca
 University of Essex
 Curesponse

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.

Keyword(s)

Medicine

Availability

URI

https://repository.li.mahidol.ac.th/handle/20.500.14594/78032

Collections

Scopus 2021