The HGF/c-MET Axis as a Critical Driver of Resistance to Androgen Suppression in Metastatic Castrate-Resistant Prostate Cancer
Technical Report,19 Sep 2015,18 Sep 2016
MICHIGAN UNIV ANN ARBOR ANN ARBOR United States
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In this Physician Research Training Award, the primary goal is to elucidate the role of the HGFc-MET axis in metastatic castration-resistant prostate cancer. During the current funding period, we have confirmed an inverse relationship between MET expression and AR signaling in prostate cancer cell lines. Our data supports negative regulation of MET by AR signaling, and we found that AR signaling inhibition in AR-positive CRPC models increased MET expression and resulted in susceptibility to ligand HGF activation. Likewise, our work over the past year showed that MET inhibition was only effective in blocking cancer phenotypes in cells with MET overexpression. Using multiple AR-positive CRPC models, as detailed in the initial proposal, we found that combined MET inhibition and enzalutamide AR antagonist treatment was more efficacious than either inhibitor alone. These data support the concept that the MET pathway may be a key mechanism of resistance in men with CRPC who undergo potent androgen signaling inhibition with abiraterone or enzalutamide.