SKI-606, a Src/Abl Inhibitor withIn vivoActivity in Colon Tumor Xenograft Models

Abstract

Src up-regulation is a common event in human cancers. In colorectal cancer, increased Src levels are an indicator of poor prognosis, and progression to metastatic disease is associated with substantial increases in Src activity. Therefore, we examined the activity of SKI-606, a potent inhibitor of Src and Abl kinases, against colon tumor lines in vitro and in s.c. tumor xenograft models. SKI-606 inhibited Src autophosphorylation with an IC 50 of f0.25 Mmol/L in HT29 cells. Phosphorylation of Tyr 925 of focal adhesion kinase, a Src substrate, was reduced by similar concentrations of inhibitor. Antiproliferative activity on plastic did not correlate with Src inhibition in either HT29 or Colo205 cells (IC 50 s, 1.5 and 2.5 Mmol/L, respectively), although submicromolar concentrations of SKI-606 inhibited HT29 cell colony formation in soft agar. SKI-606 also caused loosely aggregated Colo205 spheroids to condense into compact spheroids. On oral administration to nude mice at the lowest efficacious dose, peak plasma concentrations of f3 Mmol/L, an oral bioavailability of 18%, and a t 1/2 of 8.6 hours were observed. SKI-606 was orally active in s.c. colon tumor xenograft models and caused substantial reductions in Src autophosphorylation on Tyr 418 in HT29 and Colo205 tumors. SKI-606 inhibited HT29 tumor growth on once daily administration, whereas twice daily administration was necessary to inhibit Colo205, HCT116, and DLD1 tumor growth. These results support development of SKI-606 as a therapeutic agent for treatment of colorectal cancer. (Cancer Res 2005; 65(12): 5358-64)

Efficacy and pharmacodynamic effects of bosutinib (SKI-606), a Src/Abl inhibitor, in freshly generated human pancreas cancer xenografts

“…1B). This is consistent with previously published studies of bosutinib in colorectal xenografts (24) and breast xenografts (25) as well as other Src inhibitors in pancreas cancer mouse models (14).…”

Src family kinase activity regulates adhesion, spreading and migration of pancreatic endocrine tumour cells

“…QGP-1 show high levels of Src family activity in comparison with several cancer cell lines of different origins. Interestingly, Src activity in QGP-1 was Endocrine-Related Cancer (2007) 14 111-124 www.endocrinology-journals.org comparable with Colo205, a colon cancer cell line frequently used for studies on the role of Src in neoplastic cells (Golas et al 2005).…”

“…We observed that QGP-1 cells display very high levels of Src activity, as elevated as that of Colo205 (Fig. 1B), a colon cancer cell line that is frequently used to study the role of up-regulation of Src in cancer cells (Golas et al 2005). Although lower than in QGP-1, the activity of Src in CM cells was comparable with that of MCF-7, a breast cancer cell line in which Src is required for cell proliferation and invasiveness (Castoria et al 2001).…”

Dual targeting of Src and ER prevents acquired antihormone resistance in breast cancer cells

“…We and others have recently identified a role for Src kinase in acquired endocrine resistance in vitro [11,19], where it may regulate both proliferative and invasive responses in such cells. Data is emerging which reveals Src kinase as a novel tumour target, where its inhibition is effective at suppressing proliferation and/or metastatic events in a wide range of tumour types including CML [30,31], colon tumours [32,33] and pancreatic cancer [34,35]. Further studies [36,37] also provide compelling evidence that targeting Src may be of value in combination with existing chemotherapy to provide an augmented antitumour response.…”