4745 The non-receptor protein tyrosine kinase, SRC has been implicated as a key regulator of tumor progression and metastasis in a variety of human malignancies, and is overactivated in a number of tumor types. Specifically, colorectal hepatic metastases exhibit markedly elevated SRC kinase activity as compared with normal colonic mucosa and primary tumors, and increased activity is predictive of poor prognosis. Thus, SRC inhibitors represent an attractive therapeutic target and, as such, will be entering clinical trial as single agents for metastatic colon cancer. In the current study, we investigated whether dasatinib (BMS-354825), a novel, oral, potent, multi-targeted kinase inhibitor of SRC and BCR-ABL, when combined with oxaliplatin, could inhibit growth of established hepatic colorectal tumors. Dasatinib monotherpay has already shown efficacy, and was well tolerated, in Philidelphia-chromosome-positive chronic myeloid leukemia and acute lymphoblastic leukemia in a Phase I trial of patients who were imatinib-resistant/-intolerant; Phase II studies are ongoing in these patients. Phase I evaluation of dasatinib monotherapy in solid tumors is also ongoing. For the studies described herein, HT29 human colorectal carcinoma cells were injected directly into the liver, and treatment (dasatinib daily by oral gavage and oxaliplatin twice weekly via IP injection) was initiated 14 days later. Treatment with dasatinib alone (15mg/kg) or oxaliplatin (5mg/kg) alone reduced hepatic tumor volume by 31% and 35%, respectively. In contrast, treatment with the inhibitors combined at the same concentrations reduced hepatic tumor volume by 75%. Furthermore, treatment with dasatinib in combination with Oxaliplatin was associated with markedly decreased microvessel density, relative to either inhibitor alone. Whereas increased necrosis was evident relative to either agent alone, there was no increase in apoptosis as determined by TUNEL staining of tumor sections. Treatment with dasatinib but not oxaliplatin decreased expression of phospho SRC419, indicative of efficacy on activated SRC, demonstrating that dasatinib effectively inhibited SRC by the above-described regimen. In conclusion, the combination of oxaliplatin, currently in clinical trials for metastatic colon cancers, and a SRC inhibitor, also in clinical trials for a variety of solid tumors, could prove less toxic and more efficacious than current therapeutic regimens.