Targeting Met and VEGFR Axis in Metastatic Castration-Resistant Prostate Cancer: ‘Game Over’?

Abstract

Despite recent advances that have been made in the therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC), effective management of bone metastases remains a key goal not yet reached. The receptor tyrosine kinase MET and the vascular endothelial growth factor receptor (VEGFR) seem to play an important role in prostate cancer progression and pathological bone turnover, representing potential targets for improving clinical outcomes in mCRPC. Studies evaluating agents that target one or both these pathways have demonstrated modest activity but no improvement in overall survival. Nevertheless, this therapeutic strategy seems to still be a promising and engaging area of prostate cancer research and the interest in better understanding the MET/VEGFR axis and the mechanism of action of these inhibitors is growing. This review describes the rationale for targeting MET and VEGFR pathway in mCRPC and provides the clinical data available to date and an update on ongoing trials.

GABABR-Induced EGFR Transactivation Promotes Migration of Human Prostate Cancer Cells

“…Currently, few therapeutic options are available for patients with advanced PCa. Tyrosine kinase inhibitors, which are effective in some human malignancies (Rask-Andersen et al, 2014), have been used as single agents or in combination with chemotherapy in clinical trials in patients with castrationresistant PCa; however, the results were not promising (Jakobovits, 2008;Gallick et al, 2012;Molife et al, 2014;Ojemuyiwa et al, 2014;Modena et al, 2016). Therefore, new mechanism-based inhibitors need to be developed to treat PCa patients.…”

Choosing Kinase Inhibitors for Androgen Deprivation Therapy-Resistant Prostate Cancer

“…Although we appreciate that most of these available kinase inhibitors are designed to target one specific kinase, which can avoid side (off-target) effects caused by nonspecific inhibition of other targets important for normal cells, targeting one single kinase or pathway may not be efficient or no effect at all for the suppression of tumor development. For instance, both MET and VEGFR signaling play an important role in CRPC development [ 115 ]; the inhibition of MET and VEGFR by a multi-targeted tyrosine kinase inhibitor cabozantinib shows much stronger anti-CRPC activity than either VEGFR inhibitor axitinib or MET inhibitor crizotinib used alone [ 115 , 116 ]. We reported that TBK1 and IKKi can functionally compensate for each other.…”

“…It has been reported that both MET and VEGFR signal pathways play an important role in CRPC [ 115 ]. Dual inhibition of MET and VEGFR by cabozantinib (formerly XL184, a multi-targeted tyrosine kinase inhibitor) or the combined axitinib (VEGFR inhibitor) with crizotinib (MET inhibitor) shows strong synergistic inhibitory effect on CRPC ( Figure 2 and Table 1 ) [ 115 , 116 ].…”

Biological Issues with Cabozantinib in Bone Metastatic Renal Cell Carcinoma and Castration-Resistant Prostate Cancer

“…Cabozantinib has also been tested in patients with metastatic castration-resistant prostate cancer (CRPCa) in a Phase III clinical trial (COMET-1), where it failed to demonstrate a clinical benefit in terms of OS [13][14][15]. However, patients treated with cabozantinib showed a better bone scan response rate (42% with cabozantinib vs 3% with prednisone), bone biomarkers decrease and circulating tumor cells conversion suggesting an active effect on bone metastases.…”