November 28, 2021

Floxacin antibiotics may increase treatment of lung and bladder cancer by inhibiting RSK4

Floxacin antibiotics may improve treatment for patients with lung and bladder cancer, according to a study published in Science Translational Medicine.

Preclinical research has shown that the antibiotics floxacin inhibit the RSK4 protein kinase, thereby sensitizing lung and bladder cancer cells to chemotherapy and hindering metastasis.

Clinical research has shown that cancer patients receiving chemotherapy have a longer overall survival (OS) when they also receive treatment with levofloxacin.


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Researchers first found that RSK4 regulates chemosensitivity and controls the migration and invasion of lung and bladder cancer cells. Inhibition of RSK4 via CRISPR or RNA interference sensitized cancer cells to chemotherapy and prevented metastasis in mice.

Drug screening has shown that floxacin antibiotics can inhibit RSK4. Subsequent experiments have shown that trovafloxacin can sensitize cancer cells to chemotherapy and inhibit tumor growth in vivo and ex vivo.

Analyzes of patient samples have shown that RSK4 mRNA is overexpressed in patients with lung or bladder cancer. Additionally, lung cancer survival data showed that high expression of RSK4 mRNA was associated with a poorer prognosis.

Analysis of data from the Phase 3 SIGNIFICANT trial (ClinicalTrials.gov Identifier: NCT00005590) suggested that levofloxacin may prolong OS in patients with advanced cancers receiving chemotherapy.

The median OS was 72 months in patients who received levofloxacin and 59 months in patients who received placebo (risk ratio: 0.83; 95% CI: 0.69-0.99; P = .048).

“The sensitivity analysis showed that excluding patients who died during treatment did not change the conclusions and, therefore, this improvement in OS could not be due to a reduction in deaths from infection due to the antibacterial effect of levofloxacin, ”the researchers noted.

“Collectively, our data suggest that floxacins targeting RSK4, such as levofloxacin, could be reused for proof-of-concept combination studies with existing chemotherapies in patients with lung and bladder cancer,” said concluded the researchers.

Disclosures: This research was supported by the Cancer Research UK Imperial Center and others. Some study authors have reported affiliations with biotechnology, pharmaceutical and / or device companies. Please see the original reference for a full list of disclosures.

Reference

Chrysostomou S, Roy R, Prischi F, et al. Reused floxacins targeting RSK4 prevent drug resistance and metastasis in lung and bladder cancer. Sci Transl Med. 2021; 13 (602): eaba4627. doi: 10.1126 / scitranslmed.aba4627


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