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Song L, Morris M, Bagui T, Lee FY, Jove R, Haura EB.. Dasatinib (BMS-354825) selectively induces apoptosis in lung cancer cells dependent on epidermal growth factor receptor signaling for survival. Cancer Res 66: 5542-5548

University of South Florida, Tampa, Florida, United States
Cancer Research (Impact Factor: 9.28). 07/2006; 66(11):5542-8. DOI: 10.1158/0008-5472.CAN-05-4620
Source: PubMed

ABSTRACT Mutations of the epidermal growth factor receptor (EGFR) selectively activate Akt and signal transducer and activator of transcription (STAT) pathways that are important in lung cancer cell survival. Src family kinases can cooperate with receptor tyrosine kinases to signal through downstream molecules, such as phosphatidylinositol 3-kinase/PTEN/Akt and STATs. Based on the importance of EGFR signaling in lung cancer, the known cooperation between EGFR and Src proteins, and evidence of elevated Src activity in human lung cancers, we evaluated the effectiveness of a novel orally bioavailable Src inhibitor dasatinib (BMS-324825) in lung cancer cell lines with defined EGFR status. Here, we show that cell fate (death versus growth arrest) in lung cancer cells exposed to dasatinib is dependent on EGFR status. In cells with EGFR mutation that are dependent on EGFR for survival, dasatinib reduces cell viability through the induction of apoptosis while having minimal apoptotic effect on cell lines with wild-type (WT) EGFR. The induction of apoptosis in these EGFR-mutant cell lines corresponds to down-regulation of activated Akt and STAT3 survival proteins. In cell lines with WT or resistant EGFR mutation that are not sensitive to EGFR inhibition, dasatinib induces a G(1) cell cycle arrest with associated changes in cyclin D and p27 proteins, inhibits activated FAK, and prevents tumor cell invasion. Our results show that dasatinib could be effective therapy for patients with lung cancers through disruption of cell growth, survival, and tumor invasion. Our results suggest EGFR status is important in deciding cell fate in response to dasatinib.

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    • "Dasatinab (BMS-354825), a potent oral tyrosine Kinase inhibitor against the Src family Kinases, BCR-ABL, platelet derived growth factor receptor and c-Kit has demonstrated multiple effects on solid tumors and has been approved for use in patients with chronic myelogenous leukemia refractory or intolerant to imatinib [13] and in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia [14]. Although there are active research studies evaluating the molecular mechanisms of dasatinib on human solid tumor cells such as prostate cancer, head and neck squamous cell carcinoma, non-small cell lung cancer, breast cancer, but the true regulatory mechanisms are still not fully understood, especially in HCC [15-21]. "
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    ABSTRACT: 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 μM ~ 14.2 μM. 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.
    BMC Cancer 05/2013; 13(1):267. DOI:10.1186/1471-2407-13-267 · 3.32 Impact Factor
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    • "Shown are representative blots of three independent experiments. cancer cells posses other active pro-survival signaling pathways such as EGFR, STAT3 and c-Met [17] [30] [42] [44] [45]. "
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    ABSTRACT: BACKGROUND AND PURPOSE: Although inhibition of epidermal growth factor receptor (EGFR) signaling during radiation led to improvement of tumor control and survival, novel strategies are needed to further improve the outcome of patients with locally advanced head and neck carcinoma. Because EGFR is known to interact with c-Src kinases, the present study investigated dasatinib (BMS-354825), an inhibitor of c-Src kinases, for its efficacy in enhancing radiosensitivity of human head and neck squamous cell carcinomas (HNSCC) in vitro and examined the underlying mechanisms for this effect. MATERIALS AND METHODS: Six HNSCC lines were exposed to dasatinib, radiation, or both, and assessed for c-Src and EGFR expression, cell survival and colony forming ability. Among these cell lines, HN-5 and FaDu lines were analyzed for induction of apoptosis, cell cycle re-distribution and for nuclear localization of EGFR, γ-H2AX and 53BP1 proteins. Immuno-precipitation and Western blots were performed to analyze the levels and binding of proteins involved in cell survival, apoptosis and DNA repair pathways. Suppression of c-Src by siRNA and subsequent clonogenic assay was performed in HN-5 cells. RESULTS: All six HNSCC lines that were examined expressed high levels of c-Src. Two (HN-5 and MDA-183) expressed higher levels of EGFR than other lines. Dasatinib suppressed cell survival of all cell lines tested independent of c-Src or EGFR levels but enhanced the radiosensitivity of HN-5 and MDA-183. HN-5 and FaDu were analyzed further. Dasatinib suppressed phosphorylation of c-Src in both cell lines, but decreased repair of radiation-induced DNA damage in HN-5 cells only as evidenced by suppression of c-Abl and Nbs-1 activity, inhibition of the association between c-Src and EGFR or Her-2, prolongation of nuclear γ-H2AX and 53BP1 foci and inhibition of EGFR nuclear localization and its association with DNA-PKcs. Finally, partial suppression of c-Src resulted in a small increase in HN-5 cell radiosensitivity. CONCLUSIONS: Our data demonstrate that dasatinib induces apoptosis and blocks DNA repair in EGFR-expressing HNSCC cells and improves radiotherapy outcome. These findings warrant further investigation using in vivo tumor models for potential translation into clinical testing.
    Radiotherapy and Oncology 09/2012; 105(2). DOI:10.1016/j.radonc.2012.08.010 · 4.86 Impact Factor
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    • "Src and the related Src family kinases signal through multiple downstream intermediaries including STAT3 (Yu et al, 1995), FAK, and β-catenin (Irby et al, 2005), and Src activation has been implicated in decreased tumour cell adhesion, increased invasiveness, and increased motility (Buettner et al, 2008). Src activation has been implicated in the pathogenesis of colon (Irby et al, 1999; Kline et al, 2008), lung (Song et al, 2006), pancreas (Trevino et al, 2006), breast (Hiscox et al, 2006; Jallal et al, 2007; Morgan et al, 2009), and prostate cancer (Nam et al, 2005; Kotha et al, 2006). In uveal melanoma, Src activation has been associated with the MAP kinase pathway activation (Maat et al, 2009). "
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    ABSTRACT: Src inhibitors sensitise melanoma cells to chemotherapy in preclinical models. The combination of dasatinib and dacarbazine was tested in a phase I trial in melanoma. Patients had ECOG performance status 0-2 and normal organ function. Dacarbazine was administered on day 1 and dasatinib on day 2 through 19 of each 21-day cycle. Both were escalated from 50 mg b.i.d. of dasatinib and 800 mg m(-2) of dacarbazine. Available pre-treatment biopsies were sequenced for BRAF, NRAS, and C-Kit mutations. Dose-limiting toxicity was reached at dasatinib 70 mg b.i.d./dacarbazine 1000 mg m(-2), and was predominantly haematological. In 29 patients receiving dasatinib 70 mg b.i.d., the objective response rate (ORR) was 13.8%, the clinical benefit rate (ORR+SD) was 72.4%, the 6-month progression-free survival (PFS) was 20.7%, and the 12-month overall survival (OS) was 34.5%. Two out of three patients who were wild type for BRAF, NRAS, and c-KIT mutations had confirmed partial responses, and one had a minor response. The recommended phase II dose is dasatinib 70 mg b.i.d with dacarbazine 800 mg m(-2). PFS and OS data for dasatinib at 70 mg b.i.d. with dacarbazine compared favourably with historical controls. Preliminary data support evaluating tumour mutation status further as a biomarker of response.
    British Journal of Cancer 11/2011; 106(1):85-91. DOI:10.1038/bjc.2011.514 · 4.82 Impact Factor
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