Activity of the multikinase inhibitor dasatinib against ovarian cancer cells

Ge, Konecny; Glas, Ruth; Dering, Judy; Manivong, Kanthinh; Qi, Ji; Finn, RS; Yang, Guang; Kl, Hong; Ginther, Charles; Winterhoff, Boris; Gao, Geng; Brugge, Joan S.; Slamon, DJ

doi:10.1038/sj.bjc.6605381

Cited by 81 publications

(73 citation statements)

References 45 publications

(59 reference statements)

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“…Although dasatinib has been studied in other solid tumors such as ovarian, lung, breast (11,12), the in vitro and in vivo effects of dasatinib on thyroid cancer have as yet not been published to the best of our knowledge. Of all the kinase inhibitors in our inhibitor array, dasatinib was the focus of the present study as it is already in clinical use for other indications and no previous reports exist on the activity of dasatinib despite the availability of studies on the activity of other similar inhibitors such as AZD0530 in thyroid cancer.…”

Section: Discussionmentioning

confidence: 99%

Effect of dasatinib against thyroid cancer cell lines in vitro and a xenograft model in vivo

et al. 2012

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Abstract. Tyrosine kinase inhibitors (TKIs) have emerged as a promising class of agents against thyroid cancer. The aim of the present study was to investigate the in vitro and in vivo activity of dasatinib against a panel of thyroid cancer cell lines and explore possible mechanisms of action, using various assays and western blotting. Our results showed that dasatinib exhibits prominent cytostatic activity both in vitro and in vivo against thyroid cancer cell lines with RET/PTC rearrangement (BHP2-7) and KRAS mutation (Cal62). Although dasatinib has primarily been described as an ABL/SRCfamily kinase inhibitor, the cytostatic activity observed in the present study is mediated by several off-target effects of dasatinib, some of which have not previously been reported. These effects include a reduction in phospho-FAK, FAK, RAS, Caveolin and SYK protein levels and an increase in β-catenin protein expression, which leads to the induction of senescence, an increase in the adhesiveness of the cells, a decrease in reactive oxygen species level, and changes in the expression profile of molecules involved in cellular adhesion such as integrins. Therefore, we propose that dasatinib is an effective therapeutic agent for certain patients with thyroid cancer, and these candidate patients may be identifiable on the basis of standard genotypic analyses.

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Section: Discussionmentioning

confidence: 99%

Effect of dasatinib against thyroid cancer cell lines in vitro and a xenograft model in vivo

et al. 2012

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“…Additionally, inhibition of other unevaluated targets not associated with Src may also partly account for activity, e.g., the Btk tyrosine kinase, which has been found to be another major target of dasatinib (30). Ovarian cancer cell lines with high expression of Yes, Lyn, Eph2A but not Src, FAK, Kit, or PDGFR-β were sensitive to dasatinib, which suggests a potential role for other molecular targets (18). However, there is no evidence supporting the expression of other key targets of dasatinib, Kit and Abl, in TCC.…”

Section: Discussionmentioning

confidence: 99%

“…Cisplatin resistance induced by v-src transfection of gallbladder carcinoma cells was reversed by inhibitors of Src (15). Additionally, Src inhibition sensitizes ovarian cancer cells to both paclitaxel and platinum agents (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Dasatinib Is Preclinically Active against Src-Overexpressing Human Transitional Cell Carcinoma of the Urothelium with Activated Src Signaling

Levitt

Yamashita

Jian

et al. 2010

Molecular Cancer Therapeutics

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Dasatinib is an orally administered multitargeted kinase inhibitor that targets Src family tyrosine kinases, Abl, c-Kit, and PDGFR. A preclinical study was conducted to evaluate dasatinib alone or combined with cisplatin for human transitional cell carcinoma (TCC). Expression of Src in a human TCC tissue microarray was evaluated by immunohistochemistry. The activity of dasatinib and/or cisplatin was evaluated in six human TCC cell lines. Western blot was done to assess Src and phosphorylated-Src (p-Src) expression. The activity of dasatinib alone and in combination with cisplatin was determined in murine subcutaneous xenografts. Sixty-two percent to 75% of human TCC expressed Src. Dasatinib displayed significant antiproliferative activity at nanomolar concentrations against two human TCC cell lines (RT4 and Hu456) that exhibited high Src and p-Src expression and were cisplatin-resistant. RT4 cells were the most sensitive and displayed the highest level of Src pathway activation (p-Src/Src ratio). Dasatinib downregulated p-Src in either sensitive or resistant cells. TCC cells that were sensitive to cisplatin (5637 and TCC-SUP) were highly resistant to dasatinib and exhibited low Src expression. Dasatinib showed antitumor activity in RT4 murine xenografts, and the combination of dasatinib and cisplatin was significantly more active than placebo. Combination dasatinib plus cisplatin significantly inhibited proliferation and promoted apoptosis in vivo.In conclusion, dasatinib displayed significant preclinical antitumor activity against Src-overexpressing human TCC with active Src signaling and was highly active in combination with cisplatin in vivo. Further clinical development might be warranted in selected human subjects. Mol Cancer Ther; 9(5); 1128-35. ©2010 AACR.

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“…134 SFK inhibition can induce cancer cell apoptosis to enhance paclitaxel cytotoxicity through several signaling molecules and pathways. SFK inhibition can downregulates PI3K-AKT, 25,106,136 STAT3/5, 140 Bcl-2, 25 Bcl-x L 141 and Mcl-1, 140 and induce apoptosis [140][141][142] SFK inhibition also downregulates expression of antiapoptotic survivin. 106 SFKs can phosphorylate tumor suppressor FHIT on tyrosine 114 residue and inactivate FHIT function.…”

Section: -139mentioning

confidence: 99%

“…160,161 Increased expression of Yes, Lyn, Eph2A, caveolin-1, moesin, annexin-1 and uPA also confer increased sensitivity to dasatinib treatment in ovarian cancer. 142 Urokinase-type plasminogen activator (uPA) and EphA2 are identified as the biomarkers that could predict dasatinib response in prostate cancer. 162 Tyrosine phosphorylation of Y419 c-Src and Y118 paxillin has been indicated as the biomarkers for response to dasatinib in colon cancer.…”

mentioning

confidence: 99%

Src family kinases and paclitaxel sensitivity

Bast

2011

Cancer Biology & Therapy

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Src-family Kinases (SFKs) participate in the regulation of proliferation, differentiation, apoptosis, autophagy, adhesion, migration, invasion and angiogenesis in normal and cancer cells. Abnormal expression of SFKs has been documented in cancers that arise in breast, colon, ovary, melanocyte, gastric mucosa, head and neck, pancreas, lung and brain. Targeting SFKs in cancer cells has been shown to be a promising therapeutic strategy in solid tumors, particularly in ovarian, colon and breast cancers. Paclitaxel is one of most widely used chemotherapeutic agents for the management of ovarian, breast, lung and head and neck cancers. As a microtubulestabilizing agent, paclitaxel possesses both mitosis-dependent and mitosis-independent activities against cancer cells. A variety of mechanisms such as deregulation of P-glycoprotein, alteration of tubulin isotypes, alteration of microtubuleregulatory proteins, deregulation of apoptotic signaling pathways, mutation of tubulins and overexpression of copper transporters have been implicated in the development of primary or secondary resistance to paclitaxel. By affecting cancer cell survival, proliferation, autophagy, microtubule stability, motility, and/or angiogenesis, SFKs interact with mechanisms that regulate paclitaxel sensitivity. inhibition of SFKs can potentiate the anti-tumor activity of paclitaxel by enhancing apoptosis, autophagy and microtubule stability. Based on pre-clinical observations, administration of SFK

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Activity of the multikinase inhibitor dasatinib against ovarian cancer cells

Cited by 81 publications

References 45 publications

Effect of dasatinib against thyroid cancer cell lines in vitro and a xenograft model in vivo

Effect of dasatinib against thyroid cancer cell lines in vitro and a xenograft model in vivo

Dasatinib Is Preclinically Active against Src-Overexpressing Human Transitional Cell Carcinoma of the Urothelium with Activated Src Signaling

Src family kinases and paclitaxel sensitivity

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