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

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

doi:10.1126/SCITRANSLMED.ABA4627

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

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 PirrieClaire 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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

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.

Original language	English
Article number	eaba4627
Number of pages	17
Journal	Science Translational Medicine
Volume	13
Issue number	602
DOIs	https://doi.org/10.1126/SCITRANSLMED.ABA4627
Publication status	Published - 14 Jul 2021

Bibliographical note

Funding Information:
The authors acknowledge infrastructure support from the Cancer Research UK Imperial Centre, the Imperial Experimental Cancer Medicine Centre, and the National Institute for Health Research Imperial Biomedical Research Centre. O.E.P., M.J.S., and F.P. thank Cancer Research UK (CRUK) for funding S.C., U.M., and F.P. and CTRT for funding R.R. M.M.U.A. acknowledges CRUK funding (C33269/A11161 and C33269/A20752). S.N.Y. and M.B. acknowledge Engineering and Physical Sciences Research Council (EPSRC) grant EP/ N014529/1 supporting the EPSRC Centre for Mathematics of Precision Healthcare. D.J.P. thanks the Wellcome Trust Strategic Fund (PS3416). J.D. is funded by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001070), the U.K. Medical Research Council (FC001070), and the Wellcome Trust (FC001070).

Publisher Copyright:
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.

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Medicine(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Chrysostomou, S., Roy, R., Prischi, F., Thamlikitkul, L., Chapman, K. L., Mufti, U., Peach, R., Ding, L., Hancock, D., Moore, C., Molina-Arcas, M., Mauri, F., Pinato, D. J., Abrahams, J. M., Ottaviani, S., Castellano, L., Giamas, G., Pascoe, J., Moonamale, D., ... Pardo, O. E. (2021). Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer. Science Translational Medicine, 13(602), Article eaba4627. https://doi.org/10.1126/SCITRANSLMED.ABA4627

@article{23e38063337d4a27b5fede0034b71460,

title = "Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer",

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. ",

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

note = "Funding Information: The authors acknowledge infrastructure support from the Cancer Research UK Imperial Centre, the Imperial Experimental Cancer Medicine Centre, and the National Institute for Health Research Imperial Biomedical Research Centre. O.E.P., M.J.S., and F.P. thank Cancer Research UK (CRUK) for funding S.C., U.M., and F.P. and CTRT for funding R.R. M.M.U.A. acknowledges CRUK funding (C33269/A11161 and C33269/A20752). S.N.Y. and M.B. acknowledge Engineering and Physical Sciences Research Council (EPSRC) grant EP/ N014529/1 supporting the EPSRC Centre for Mathematics of Precision Healthcare. D.J.P. thanks the Wellcome Trust Strategic Fund (PS3416). J.D. is funded by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001070), the U.K. Medical Research Council (FC001070), and the Wellcome Trust (FC001070). Publisher Copyright: Copyright {\textcopyright} 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.",

year = "2021",

month = jul,

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doi = "10.1126/SCITRANSLMED.ABA4627",

language = "English",

volume = "13",

journal = "Science Translational Medicine",

issn = "1946-6234",

publisher = "American Association for the Advancement of Science",

number = "602",

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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 & Pardo, OE 2021, 'Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer', Science Translational Medicine, vol. 13, no. 602, eaba4627. https://doi.org/10.1126/SCITRANSLMED.ABA4627

TY - JOUR

T1 - Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer

AU - Chrysostomou, Stelios

AU - Roy, Rajat

AU - Prischi, Filippo

AU - Thamlikitkul, Lucksamon

AU - Chapman, Kathryn L.

AU - Mufti, Uwais

AU - Peach, Robert

AU - Ding, Laifeng

AU - Hancock, David

AU - Moore, Christopher

AU - Molina-Arcas, Miriam

AU - Mauri, Francesco

AU - Pinato, David J.

AU - Abrahams, Joel M.

AU - Ottaviani, Silvia

AU - Castellano, Leandro

AU - Giamas, Georgios

AU - Pascoe, Jennifer

AU - Moonamale, Devmini

AU - Pirrie, Sarah

AU - Gaunt, Claire

AU - Billingham, Lucinda

AU - Steven, Neil M.

AU - Cullen, Michael

AU - Hrouda, David

AU - Winkler, Mathias

AU - Post, John

AU - Cohen, Philip

AU - Salpeter, Seth J.

AU - Bar, Vered

AU - Zundelevich, Adi

AU - Golan, Shay

AU - Leibovici, Dan

AU - Lara, Romain

AU - Klug, David R.

AU - Yaliraki, Sophia N.

AU - Barahona, Mauricio

AU - Wang, Yulan

AU - Downward, Julian

AU - Skehel, J. Mark

AU - Ali, Maruf M.U.

AU - Seckl, Michael J.

AU - Pardo, Olivier E.

N1 - Funding Information: The authors acknowledge infrastructure support from the Cancer Research UK Imperial Centre, the Imperial Experimental Cancer Medicine Centre, and the National Institute for Health Research Imperial Biomedical Research Centre. O.E.P., M.J.S., and F.P. thank Cancer Research UK (CRUK) for funding S.C., U.M., and F.P. and CTRT for funding R.R. M.M.U.A. acknowledges CRUK funding (C33269/A11161 and C33269/A20752). S.N.Y. and M.B. acknowledge Engineering and Physical Sciences Research Council (EPSRC) grant EP/ N014529/1 supporting the EPSRC Centre for Mathematics of Precision Healthcare. D.J.P. thanks the Wellcome Trust Strategic Fund (PS3416). J.D. is funded by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001070), the U.K. Medical Research Council (FC001070), and the Wellcome Trust (FC001070). Publisher Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.

PY - 2021/7/14

Y1 - 2021/7/14

N2 - 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.

AB - 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.

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U2 - 10.1126/SCITRANSLMED.ABA4627

DO - 10.1126/SCITRANSLMED.ABA4627

M3 - Article

C2 - 34261798

AN - SCOPUS:85111713891

SN - 1946-6234

VL - 13

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 602

M1 - eaba4627

ER -

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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