Targeting Src Family Kinases Inhibits Growth and Lymph Node Metastases of Prostate Cancer in an Orthotopic Nude Mouse Model

Abstract

Aberrant expression and/or activity of members of the Src family of nonreceptor protein tyrosine kinases (SFK) are commonly observed in progressive stages of human tumors. In prostate cancer, two SFKs (Src and Lyn) have been specifically implicated in tumor growth and progression. However, there are no data in preclinical models demonstrating potential efficacy of Src inhibitors against prostate cancer growth and/ or metastasis. In this study, we used the small molecule SFK/ Abl kinase inhibitor dasatinib, currently in clinical trials for solid tumors, to examine in vitro and in vivo effects of inhibiting SFKs in prostate tumor cells. In vitro, dasatinib inhibits both Src and Lyn activity, resulting in decreased cellular proliferation, migration, and invasion. In orthotopic nude mouse models, dasatinib treatment effectively inhibits expression of activated SFKs, resulting in inhibition of both tumor growth and development of lymph node metastases in both androgen-sensitive and androgen-resistant tumors. In primary tumors, SFK inhibition leads to decreased cellular proliferation (determined by immunohistochemistry for proliferating cell nuclear antigen). In vitro, small interfering RNA (siRNA)-mediated inhibition of Lyn affects cellular proliferation; siRNA inhibition of Src affects primarily cellular migration. Therefore, we conclude that SFKs are promising therapeutic targets for treatment of human prostate cancer and that Src and Lyn activities affect different cellular functions required for prostate tumor growth and progression. [Cancer Res 2008;68(9):3323-33]

Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis

“…This point is critical to our in vivo studies as it allows for PSA levels to be used as a surrogate marker for tumour growth in bone in response to this therapy. Also of interest, despite recent literature demonstrating the importance of the SFK member, lyn, in regulating proliferation of PC-3 CaP cells (Park et al, 2008); we show that lyn phosphorylation is unaffected in C4-2B cells on treatment with dasatinib. Thus implying that lyn inactivation is not involved in the inhibition of proliferation by dasatinib in these cells.…”

“…It has been previously reported that lyn has a prominent role in the control of proliferation of PC-3 CaP cells in vitro whereas src played a more significant role as a mediator of migration (Park et al, 2008). Therefore in our subsequent experiments, we investigated the effects of dasatinib on phosphorylation of lyn and src, specifically, in C4-2B cells.…”

“…Recently, dasatinib has been shown to inhibit proliferation, cell adhesion, migration and invasion of CaP cells in vitro (Lombardo et al, 2004;Nam et al, 2005). Furthermore, dasatinib decreased the growth of PC-3 CaP cells injected orthotopically, reduced the number of metastases and inhibited growth at the metastatic site (Park et al, 2008;Yano et al, 2008).…”

Activity of tyrosine kinase inhibitor Dasatinib in neuroblastoma cells in vitro and in orthotopic mouse model

“…However, we treated animals with a dose [30 mg/(kg day)] higher than that utilized in CML pre-clinical models 19 and in other solid tumours. 33 In addition, HTLA-230 tumours were vascularized and Dasatinib treatment did not induce any significant change, at least as assessed by microscopic observation. Using SY5Y cells in vivo in the orthotopic model, we failed to demonstrate Dasatinib antitumour activity at 30 mg/(kg day) and at 60 mg/(kg day) when starting treatment 7 days after transplantation.…”

Microfluidic single cell arrays to interrogate signalling dynamics of individual, patient-derived hematopoietic stem cells

“…14,15 Studies have shown that dasatinib specifically interrupts cell motility in other forms of cancer including prostate, melanoma, and Ewing sarcoma. [16][17][18][19] It is likely that a similar process occurs in CML cells; a subject currently under investigation. Whilst these cells are resistant to apoptosis, dasatinib does exert a significant inhibitory effect upon 5 cell motility by blocking src kinase mediated activity.…”