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Open Access Highly Accessed Research article

Efficacy of c-Met inhibitor for advanced prostate cancer

William H Tu1*, Chunfang Zhu1, Curtis Clark1, James G Christensen2 and Zijie Sun1*

Author affiliations

1 Department of Urology and Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305-5328, USA

2 Department of Cancer Research, Pfizer Global Research and Development, La Jolla Laboratories, La Jolla, CA 92121, USA

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Citation and License

BMC Cancer 2010, 10:556  doi:10.1186/1471-2407-10-556

Published: 14 October 2010

Abstract

Background

Aberrant expression of HGF/SF and its receptor, c-Met, often correlates with advanced prostate cancer. Our previous study showed that expression of c-Met in prostate cancer cells was increased after attenuation of androgen receptor (AR) signalling. This suggested that current androgen ablation therapy for prostate cancer activates c-Met expression and may contribute to development of more aggressive, castration resistant prostate cancer (CRPC). Therefore, we directly assessed the efficacy of c-Met inhibition during androgen ablation on the growth and progression of prostate cancer.

Methods

We tested two c-Met small molecule inhibitors, PHA-665752 and PF-2341066, for anti-proliferative activity by MTS assay and cell proliferation assay on human prostate cancer cell lines with different levels of androgen sensitivity. We also used renal subcapsular and castrated orthotopic xenograft mouse models to assess the effect of the inhibitors on prostate tumor formation and progression.

Results

We demonstrated a dose-dependent inhibitory effect of PHA-665752 and PF-2341066 on the proliferation of human prostate cancer cells and the phosphorylation of c-Met. The effect on cell proliferation was stronger in androgen insensitive cells. The c-Met inhibitor, PF-2341066, significantly reduced growth of prostate tumor cells in the renal subcapsular mouse model and the castrated orthotopic mouse model. The effect on cell proliferation was greater following castration.

Conclusions

The c-Met inhibitors demonstrated anti-proliferative efficacy when combined with androgen ablation therapy for advanced prostate cancer.