Modulation of cabozantinib efficacy by the prostate tumor microenvironment

Area of Science:

• Oncology
• Cancer Biology
• Pharmacology

Background:

• The tumor microenvironment (TME) is critical in prostate cancer (PCa) metastasis and drug resistance.
• Cabozantinib, a tyrosine kinase inhibitor (TKI), showed limited survival benefit in advanced PCa despite preclinical activity.
• Understanding cabozantinib's mechanism in the TME is crucial for optimizing TKI therapy and patient selection.

Purpose of the Study:

• To investigate the mechanism of action of cabozantinib within the PCa tumor microenvironment.
• To explore the potential pro-tumorigenic effects of cabozantinib on host cells.
• To identify biomarkers for patient selection in TKI-based therapies for advanced PCa.

Main Methods:

• Assessed cabozantinib's IC50 in PCa epithelia and various fibroblast populations.
• Evaluated cabozantinib's effect on tumor engraftment and bone turnover in PCa mouse models.
• Analyzed M1 macrophage polarization and monocyte reprogramming in response to cabozantinib in mice and PCa patients.

Main Results:

• Cabozantinib exhibited significantly lower IC50 values in fibroblasts and macrophages compared to PCa epithelia.
• Pre-treatment with cabozantinib enhanced tumor engraftment and modulated bone turnover in preclinical models.
• Cabozantinib altered M1 macrophage polarization and induced monocyte reprogramming correlated with bone response in patients.

Conclusions:

• Cabozantinib may exert pro-tumorigenic effects via host responses within the TME, particularly impacting bone turnover and macrophage polarization.
• Monocyte reprogramming serves as a potential biomarker for therapeutic bone response, aiding early patient selection.
• Re-evaluation of TKI strategies, considering TME responses, is warranted for selecting appropriate PCa patient populations.