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Updated: Mar 26, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Mechanistic Support for Combined MET and AR Blockade in Castration-Resistant Prostate Cancer
Yuanyuan Qiao1, Felix Y Feng2, Yugang Wang3
1Michigan Center for Translational Pathology; Department of Pathology; Comprehensive Cancer Center.
Abstract:
A recent phase III trial of the MET kinase inhibitor cabozantinib in men with castration-resistant prostate cancer (CRPC) failed to meet its primary survival end point; however, most men with CRPC have intact androgen receptor (AR) signaling. As previous work supports negative regulation of MET by AR signaling, we hypothesized that intact AR signaling may have limited the efficacy of cabozantinib in some of these patients. To assess the role of AR signaling on MET inhibition, we first performed an in silico analysis of human CRPC tissue samples stratified by AR signaling status ((+) or (-)), which identified MET expression as markedly increased in AR(-) samples. In vitro, AR signaling inhibition in AR(+) CRPC models increased MET expression and resulted in susceptibility to ligand (HGF) activation. Likewise, MET inhibition was only effective in blocking cancer phenotypes in cells with MET overexpression. Using multiple AR(+) CRPC in vitro and in vivo models, we showed that combined cabozantinib and enzalutamide (AR antagonist) treatment was more efficacious than either inhibitor alone. These data provide a compelling rationale to combine AR and MET inhibition in CRPC and may explain the negative results of the phase III cabozantinib study in CRPC. Similarly, the expression of MET in AR(-) disease, whether due to AR inhibition or loss of AR signaling, suggests potential utility for MET inhibition in select patients with AR therapy resistance and in AR(-) prostate cancer.
Insights
Androgen receptor (AR) signaling impacts MET expression in castration-resistant prostate cancer (CRPC). Combining AR and MET inhibitors shows promise for treating AR-positive CRPC, potentially improving outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Prostate Cancer Research
Background:
- Cabozantinib, a MET kinase inhibitor, failed to meet primary survival endpoints in a phase III trial for castration-resistant prostate cancer (CRPC).
- Most CRPC patients retain intact androgen receptor (AR) signaling, which negatively regulates MET.
- Intact AR signaling may have limited cabozantinib's efficacy in some CRPC patients.
Purpose of the Study:
- To investigate the role of AR signaling in MET inhibition efficacy in CRPC.
- To explore the potential of combining AR and MET inhibition strategies for CRPC treatment.
Main Methods:
- In silico analysis of human CRPC tissue samples stratified by AR signaling status.
- In vitro studies using AR-positive CRPC models to assess MET expression and susceptibility to MET inhibition after AR signaling modulation.
- In vitro and in vivo experiments combining cabozantinib (MET inhibitor) and enzalutamide (AR antagonist) in AR-positive CRPC models.
Main Results:
- MET expression was significantly increased in AR-negative CRPC samples.
- Inhibition of AR signaling in AR-positive CRPC models led to increased MET expression and sensitivity to HGF activation.
- MET inhibition was effective only in blocking cancer phenotypes in cells with MET overexpression.
- Combined cabozantinib and enzalutamide treatment demonstrated superior efficacy compared to either agent alone in AR-positive CRPC models.
Conclusions:
- These findings provide a strong rationale for combining AR and MET inhibition in CRPC treatment.
- The study may explain the negative outcomes of previous cabozantinib trials in CRPC.
- MET inhibition holds potential utility for AR-negative prostate cancer and patients resistant to AR-targeted therapies.
