Dasatinib (BMS-354825)

Dasatinib is a small-molecule inhibitor of both the Src and Bcr-Abl tyrosine kinases with IC₅₀ values of 0.5 nM and 1 nM.  The oncogenic tyrosine kinase Bcr-Abl, plays a critical role in the pathogenesis of CML (chronic myelogenous leukemia). In most CML patients, the kinase domain of Bcr-Abl have mutations that interfere with binding to the first Abl kinase inhibitor, but Dasatinib bind more efficiently to these Abl kinase mutations and thus more effective than imatinib in inhibiting the proliferation cells with wild-type Bcr-Abl or Bcr-Abl mutants.

References
1. Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells. S Nam, D Kim, JQ Cheng, S Zhang, JH Lee, R Buettner. Cancer Research. 2005
2. Dasatinib (BMS-354825) selectively induces apoptosis in lung cancer cells dependent on epidermal growth factor receptor signaling for survival. L Song, M Morris, T Bagui, FY Lee, R Jove, EB Haura . Cancer Research. 2006

The Src/ABL kinase inhibitor dasatinib (BMS-354825) inhibits function of normal human T-lymphocytes in vitro.[Pubmed:18395492]

Clin Immunol. 2008 Jun;127(3):330-9.

Dasatinib (BMS-354825) is a Src/ABL tyrosine kinase inhibitor currently approved for the treatment of chronic myeloid leukemia. Dasatinib has increased potency against ABL compared to the current therapy imatinib, and is effective in many cases where disease is resistant to imatinib. Dasatinib also inhibits many Src-family tyrosine kinases. We have demonstrated in this study that dasatinib is able to block the function of normal human T-lymphocytes in vitro at clinically relevant concentrations. T-cell functions including proliferation, activation and cytokine production were all uniformly inhibited in the presence of dasatinib. We also demonstrated inhibition of TCR signalling through Src-family kinase LCK, and predicted that inhibition of LCK and other kinases involved in T-cell signalling by dasatinib is responsible for the suppression of T-cell function. These findings raise the concern about potential T-cell inhibition in patients taking dasatinib, and suggest a possible application for the treatment of T-cell mediated immune disorders.

Phase II study of dasatinib (BMS-354825) in patients with metastatic adenocarcinoma of the pancreas.[Pubmed:24072218]

Oncologist. 2013;18(10):1091-2.

BACKGROUND: Src, EphA2, and platelet-derived growth factor receptors alpha and beta are dysregulated in pancreatic ductal adenocarcinoma (PDAC). METHODS: Dasatinib is an oral multitarget tyrosine kinase inhibitor that targets BCR-ABL, c-Src, c-KIT, platelet-derived growth factor receptor beta, and EphA2. We conducted a phase II, single-arm study of dasatinib as first-line therapy in patients with metastatic PDAC. METHODS: Dasatinib (100 mg twice a day, later reduced to 70 mg twice a day because of toxicities) was orally administered continuously on a 28-day cycle. The primary endpoint was overall survival (OS). Response was measured using the Response Evaluation Criteria in Solid Tumors. Circulating tumor cells (CTCs) were also collected. RESULTS: Fifty-one patients enrolled in this study. The median OS was 4.7 months (95% confidence interval [CI]: 2.8-6.9 months). Median progression-free survival was 2.1 months (95% CI: 1.6-3.2 months). In 34 evaluable patients, the best response achieved was stable disease in 10 patients (29.4%). One patient had stable disease while on treatment for 20 months. The most common nonhematologic toxicities were fatigue and nausea. Edema and pleural effusions occurred in 29% and 6% of patients, respectively. The number of CTCs did not correlate with survival. CONCLUSION: Single-agent dasatinib does not have clinical activity in metastatic PDAC.

Phase I study of dasatinib (BMS-354825) in Japanese patients with solid tumors.[Pubmed:21781226]

Cancer Sci. 2011 Nov;102(11):2058-64.

Dasatinib is a potent oral inhibitor of tyrosine kinases including the SRC family kinases, which are activated in tumors, and implicated in invasion and bone metastasis. This phase I dose-escalation study assessed safety, tolerability, maximum tolerated dose (MTD), antitumor activity, pharmacokinetics and pharmacodynamics in Japanese patients with refractory, advanced solid tumors. Dasatinib was administered once daily at 100, 150 and 200 mg/day. Sixteen patients were treated with dasatinib in the following doses: 100 mg (nine patients), 150 mg (three patients) and 200 mg (four patients). The most frequent adverse events (AE; >/= 50%) were anorexia, fatigue, pleural effusion, anemia, constipation, diarrhea, vomiting and increased aspartate aminotransferase (AST). The most frequent AE of grade >/= 3 (>/= 10%) were anemia, decreased lymphocyte count, fatigue and increased blood magnesium. Dose-limiting toxicities were observed in two patients: grade 2 pleural effusion and bronchial wall thickening at the 100-mg level and grade 3 dyspnea at the 200-mg level. In addition, grade 2 pleural effusion was observed in all four patients treated with 200 mg. Therefore, 150 mg was determined to be the MTD. The pharmacokinetic parameters were comparable among the dose levels. As a pharmacodynamic study, markers of bone metabolism were assessed. Bone resorption markers, NTx and TRACP-5b, showed a decrease of 46.3% and 22.2%, respectively. No objective responses were observed, but three patients had stable disease that lasted for over 6 months. In this study population, the safety profile of dasatinib was generally acceptable and 150 mg of dasatinib administered once daily was determined to be the MTD.

Molecular mechanisms of action and potential biomarkers of growth inhibition of dasatinib (BMS-354825) on hepatocellular carcinoma cells.[Pubmed:23721490]

BMC Cancer. 2013 May 30;13:267.

BACKGROUND: Molecular targeted therapy has emerged as a promising treatment of Hepatocellular carcinoma (HCC). One potential target is the Src family Kinase (SFK). C-Src, a non-receptor tyrosine kinase is a critical link of multiple signal pathways that regulate proliferation, invasion, survival, metastasis, and angiogenesis. In this study, we evaluated the effects of a novel SFK inhibitor, Dasatinib (BMS-354825), on SFK/FAK/p130CAS, PI3K/PTEN/Akt/mTOR, Ras/Raf/MAPK and Stats pathways in 9 HCC cell lines. METHODS: Growth inhibition was assessed by MTS assay. EGFR, Src and downstream proteins FAK, Akt, MAPK42/44, Stat3 expressions were measured by western blot. Cell adhesion, migration and invasion were performed with and without dasatinib treatment. RESULTS: The IC50 of 9 cell lines ranged from 0.7 muM ~ 14.2 muM. In general the growth inhibition by dasatinib was related to total Src (t-Src) and the ratio of activated Src (p-Src) to t-Src. There was good correlation of the sensitivity to dasatinib and the inhibition level of p-Src, p-FAK576/577 and p-Akt. No inhibition was found on Stat3 and MAPK42/44 in all cell lines. The inhibition of cell adhesion, migration and invasion were correlated with p-FAK inhibition. CONCLUSION: Dasatinib inhibits the proliferation, adhesion, migration and invasion of HCC cells in vitro via inhibiting of Src tyrosine kinase and affecting SFK/FAK and PI3K/PTEN/Akt, but not Ras/Raf/MEK/ERK and JAK/Stat pathways. T-Src and p-Src/t-Src may be useful biomarkers to select HCC patients for dasatinib treatment.