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.

• Authors: 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
• Journal: Science translational medicine (Sci Transl Med) Vol. 13 Issue 602 (07 14 2021) ISSN: 1946-6242 [Electronic] United States
• PMID: 34261798 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Ribosomal Protein S6 Kinases, 90-kDa

Topics

• Animals
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic
• Humans
• Lung (metabolism)
• Lung Neoplasms (drug therapy, genetics)
• Mice
• Ribosomal Protein S6 Kinases, 90-kDa (genetics, metabolism)
• Urinary Bladder Neoplasms (drug therapy, genetics)