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

DOI: 10.1126/scitranslmed.aba4627 DOI Help

Authors: Stelios Chrysostomou (Imperial College London) , Rajat Roy (Imperial College London) , Filippo Prischi (University of Essex; Imperial College London) , Lucksamon Thamlikitkul (Imperial College London; Mahidol University,) , Kathryn L. Chapman (Imperial College London; Domainex Ltd) , Uwais Mufti (Imperial College London) , Robert Peach (Imperial College London; University Hospital Würzburg) , Laifeng Ding (Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences) , David Hancock (The Francis Crick Institute) , Christopher Moore (The Francis Crick Institute) , Miriam Molina-Arcas (The Francis Crick Institute) , Francesco Mauri (Imperial College London) , David J. Pinato (Imperial College London) , Joel M. Abrahams (Imperial College London) , Silvia Ottaviani (Imperial College London) , Leandro Castellano (Imperial College London) , Georgios Giamas (University of Sussex) , Jennifer Pascoe (University Hospitals Birmingham NHS Foundation Trust) , Devmini Moonamale (Imperial College London) , Sarah Pirrie (University of Birmingham) , Claire Gaunt (University of Birmingham) , Lucinda Billingham (University of Birmingham) , Neil M. Steven (University Hospitals Birmingham NHS Foundation Trus) , Michael Cullen (University Hospitals Birmingham NHS Foundation Trus) , David Hrouda (Charing Cross Hospital) , Mathias Winkler (Charing Cross Hospital) , John Post (University of Dundee) , Philip Cohen (University of Dundee) , Seth J. Salpeter (Curesponse,) , Vered Bar (Curesponse) , Adi Zundelevich (Curesponse) , Shay Golan (Rabin Medical Center) , Dan Leibovici (Kaplan Medical Center) , Romain Lara (Imperial College London; AstraZeneca) , David R. Klug (Imperial College London) , Sophia N. Yaliraki (Imperial College London) , Mauricio Barahona (Imperial College London) , Yulan Wang (Nanyang Technological University) , Julian Downward (The Francis Crick Institute) , J. Mark Skehel (MRC Laboratory of Molecular Biology) , Maruf M. U. Ali (Imperial College London) , Michael J. Seckl (Imperial College London) , Olivier E. Pardo (Imperial College London)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Science Translational Medicine , VOL 13

State: Published (Approved)
Published: July 2021
Diamond Proposal Number(s): 9424

Abstract: Lung and bladder cancers are mostly incurable due to early development of drug resistance and metastatic dissemination. Hence, better 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, either through RNA interference or CRISPR, sensitised 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 tumour 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 auto-inhibitory mechanism involving the RSK4’s hydrophobic motif. Last, we show that patients undergoing chemotherapy and adhering to prophylactic levofloxacin in the large placebo-controlled randomised phase 3 SIGNIFICANT Trial had significantly (p =0.048) increased long-term overall survival times. Hence, we suggest that RSK4 inhibition may represent an effective therapeutic strategy for treating lung and bladder cancer.

Diamond Keywords: Lung Cancer; Bladder Cancer

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I24-Microfocus Macromolecular Crystallography

Added On: 28/07/2021 10:05

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Genetics Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)