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

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 ORCID: https://orcid.org/0000-0002-8830-9947, 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 and Pardo, OE, 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 (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.

Item Type:	Journal article
Publication Title:	Science Translational Medicine
Creators:	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., Pirrie, S., Gaunt, C., Billingham, L., Steven, N.M., Cullen, M., Hrouda, D., Winkler, M., Post, J., Cohen, P., Salpeter, S.J., Bar, V., Zundelevich, A., Golan, S., Leibovici, D., Lara, R., Klug, D.R., Yaliraki, S.N., Barahona, M., Wang, Y., Downward, J., Skehel, J.M., Ali, M.M.U., Seckl, M.J. and Pardo, O.E.
Publisher:	American Association for the Advancement of Science
Date:	14 July 2021
Volume:	13
Number:	602
ISSN:	1946-6234
Identifiers:	Number Type 10.1126/scitranslmed.aba4627 DOI 1537615 Other
Rights:	This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Translational Medicine in Vol 13, Issue 602 on 14 July 2021, DOI: 10.1126/scitranslmed.aba4627
Divisions:	Schools > School of Science and Technology
Record created by:	Laura Ward
Date Added:	14 Apr 2022 09:14
Last Modified:	14 Apr 2022 09:14
URI:	https://irep.ntu.ac.uk/id/eprint/46131

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