Research ArticleCancer

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

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Science Translational Medicine  14 Jul 2021:
Vol. 13, Issue 602, eaba4627
DOI: 10.1126/scitranslmed.aba4627

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Anticancer antibiotics

Lung and bladder cancers are difficult to treat because of the development of drug-refractory metastases. Chrysostomou et al. show that the p90 ribosomal protein S6 kinase 4 (RSK4) is involved in the development of chemotherapy resistance and metastatic invasion in both in vitro and in vivo models. Identification of a binding site for floxacin antibiotics on RSK4 led to the finding that trovofloxacin enhanced cisplatin efficacy in mouse models of lung and bladder cancer. Combined with the finding that levofloxacin improved patient survival in a large clinical trial, this work suggests that floxacins may be repurposable against lung and bladder cancers.

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.

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