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Updated: Jun 8, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Efficacy of c-Met inhibitor for advanced prostate cancer
William H Tu1, Chunfang Zhu, Curtis Clark
1Department of Urology, Stanford University School of Medicine, Stanford, CA 94305-5328, USA. wtu1@stanford.edu
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.
Insights
Targeting c-Met with inhibitors like PF-2341066 shows promise for advanced prostate cancer. Combining c-Met inhibition with androgen ablation therapy effectively reduced tumor growth, especially in castration-resistant prostate cancer (CRPC).
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Aberrant HGF/SF and c-Met signaling is linked to advanced prostate cancer.
- Androgen receptor (AR) signaling attenuation increases c-Met expression, potentially driving castration-resistant prostate cancer (CRPC).
- Androgen ablation therapy may inadvertently promote CRPC by activating c-Met.
Purpose of the Study:
- To evaluate the efficacy of c-Met inhibition combined with androgen ablation in prostate cancer.
- To assess the impact on tumor growth and progression in preclinical models.
Main Methods:
- Tested two c-Met inhibitors (PHA-665752, PF-2341066) using MTS and proliferation assays on prostate cancer cell lines.
- Utilized renal subcapsular and castrated orthotopic xenograft mouse models to assess in vivo efficacy.
- Evaluated effects on cell proliferation and c-Met phosphorylation.
Main Results:
- Both c-Met inhibitors demonstrated dose-dependent inhibition of prostate cancer cell proliferation and c-Met phosphorylation.
- Inhibitory effects were more pronounced in androgen-insensitive cells.
- PF-2341066 significantly reduced tumor growth in mouse models, with enhanced efficacy after castration.
Conclusions:
- c-Met inhibitors exhibit anti-proliferative activity against advanced prostate cancer.
- Combining c-Met inhibition with androgen ablation therapy is a promising strategy for treating prostate cancer, including CRPC.
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