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.

Purpose: The potential role of prostatic-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) in non-prostate cancer tumors has shown promising results. We examined the performance of dynamic ⁶⁸Ga-PSMA-11 PET/CT (DPSMA) for the evaluation of localized renal mass. Methods: A prospective case series of patients with a newly diagnosed renal mass who were referred for surgery. DPSMA was performed in a standardized manner before surgery. The final surgical histology served as the standard of reference. PSMA expression in the tumor vasculature was assessed and staining intensity was scored. Tracer uptake and PSMA expression were compared between benign and malignant tissue. Results: Of 29 enhancing renal masses evaluated in 27 patients, 24 (83%) were malignant lesions. The median mean standardized uptake value (SUVmean) of benign and malignant lesions was 2.3 (IQR 2.2-2.7) and 6.8 (IQR 4.2-10.2), respectively (P = 0.009). Median SUV_max of benign and malignant lesions was 3.8 (IQR 3.3-4.5) and 9.4 (IQR 5.4-15.8), respectively (P = 0.01), respectively. The median washout coefficient (K2) was significantly lower in malignant lesions compared to benign lesions (0.16 versus 0.80, P = 0.006). Positive PSMA staining was found in 20/24 malignant lesions and 2/5 benign lesions (P = 0.04). Conclusion: This pilot study demonstrated DPSMA uptake and kinetics in localized renal masses. Increased ⁶⁸Ga-PSMA-11 tracer uptake and intra-tumoral retention correlate with PSMA expression in malignant renal tumors compared with benign renal masses, supporting further assessment of DPSMA as a potential tool for evaluating localized renal masses.