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Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer
Stelios Chrysostomou1, Rajat Roy1, Filippo Prischi2,3
1Division of Cancer, Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK.
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.
Insights
Researchers identified RSK4 as a driver of drug resistance and metastasis in lung and bladder cancers. Inhibiting RSK4 with trovafloxacin or levofloxacin improved chemotherapy effectiveness and patient survival.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Lung and bladder cancers often resist treatment due to early drug resistance and metastasis.
- Novel therapeutic strategies are crucial for improving patient outcomes in these cancers.
Purpose of the Study:
- To identify novel therapeutic targets for lung and bladder cancers.
- To investigate the role of RSK4 in cancer progression and drug resistance.
- To evaluate RSK4 inhibitors as a potential treatment strategy.
Main Methods:
- RNA interference and CRISPR were used to silence RSK4.
- Drug screening identified floxacin antibiotics as RSK4 inhibitors.
- X-ray crystallography and biochemical analyses elucidated the drug-target interaction.
- In vitro, in vivo, and ex vivo models were utilized, including xenografts and explants.
- Analysis of data from the phase 3 SIGNIFICANT trial.
Main Results:
- RSK4 silencing sensitized cancer cells to chemotherapy and reduced metastasis in vitro and in vivo.
- Trovafloxacin effectively inhibited RSK4, mimicking the effects of RSK4 silencing.
- Structural and mechanistic studies revealed trovafloxacin's allosteric inhibition of RSK4.
- Patients receiving levofloxacin in the SIGNIFICANT trial showed improved long-term overall survival.
Conclusions:
- RSK4 is a key promoter of drug resistance and metastasis in lung and bladder cancers.
- RSK4 inhibition, particularly with floxacin antibiotics like trovafloxacin and levofloxacin, represents a promising therapeutic strategy.
- Targeting RSK4 may enhance chemotherapy efficacy and improve survival rates for patients with lung and bladder cancers.
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