Identification of candidate predictive and surrogate molecular markers for dasatinib in prostate cancer: Rationale for patient selection and efficacy monitoring

Wang, Xi-De; Reeves, Karen A.; Luo, Feng; Xu, Lian; Lee, Francis; Clark, Edwin; Huang, Fei

doi:10.1186/gb-2007-8-11-r255

Cited by 79 publications

(85 citation statements)

References 41 publications

(55 reference statements)

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“…Earlier reports have shown that high expression of annexin-1, caveolin-1, caveolin-2, moesin, and uPA, as well as low expression of IGFBP2, was associated with the in vitro response to dasatinib in breast, lung, and prostate cancer cells (Finn et al, 2007;Huang et al, 2007;Wang et al, 2007). Here, we explored the association between the various biomarkers implicated in Src signalling pathways and the in vitro response to dasatinib in 73 human cancer cell lines, including the current 34 ovarian cancer cell lines and 39 breast cancer cell lines that have been published earlier (Finn et al, 2007).…”

Section: Predictors Of Dasatinib Response In Vitromentioning

confidence: 99%

Activity of the multikinase inhibitor dasatinib against ovarian cancer cells

Glas

Dering

et al. 2009

Br J Cancer

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BACKGROUND: Here, we explore the therapeutic potential of dasatinib, a small-molecule inhibitor that targets multiple cytosolic and membrane-bound tyrosine kinases, including members of the Src kinase family, EphA2, and focal adhesion kinase for the treatment of ovarian cancer. METHODS: We examined the effects of dasatinib on proliferation, invasion, apoptosis, cell-cycle arrest, and kinase activity using a panel of 34 established human ovarian cancer cell lines. Molecular markers for response prediction were studied using gene expression profiling. Multiple drug effect/combination index (CI) isobologram analysis was used to study the interactions with chemotherapeutic drugs. RESULTS: Concentration-dependent anti-proliferative effects of dasatinib were seen in all ovarian cancer cell lines tested, but varied significantly between individual cell lines with up to a 3 log-fold difference in the IC 50 values (IC 50 range: 0.001 -11.3 mmol l À1 ). Dasatinib significantly inhibited invasion, and induced cell apoptosis, but less cell-cycle arrest. At a wide range of clinically achievable drug concentrations, additive and synergistic interactions were observed for dasatinib plus carboplatin (mean CI values, range: 0.73 -1.11) or paclitaxel (mean CI values, range: 0.76 -1.05). In this study, 24 out of 34 (71%) representative ovarian cancer cell lines were highly sensitive to dasatinib, compared with only 8 out of 39 (21%) representative breast cancer cell lines previously reported. Cell lines with high expression of Yes, Lyn, Eph2A, caveolin-1 and 2, moesin, annexin-1, and uPA were particularly sensitive to dasatinib. CONCLUSIONS: These data provide a clear biological rationale to test dasatinib as a single agent or in combination with chemotherapy in patients with ovarian cancer.

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Section: Predictors Of Dasatinib Response In Vitromentioning

confidence: 99%

Activity of the multikinase inhibitor dasatinib against ovarian cancer cells

Glas

Dering

et al. 2009

Br J Cancer

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“…In addition, a baseline pharmacodiagnostic sample would be simpler to obtain from a routine diagnostic biopsy, for example, as opposed to posttreatment (pharmacodynamic) signatures where a separate biopsy procedure would be required. When comparing the pancreas cancer susceptibility gene signature for bosutinib described here to that for breast cancer (18) and prostate cancer (19) with dasatinib, we did not find shared genes. There are several possibilities to explain this difference.…”

Section: Discussionmentioning

confidence: 98%

“…The most obvious include different biology of breast and prostate cancer versus pancreas cancer, and cell lines versus cancer tissue that was explanted directly from the operating room into mice. In addition, it should be noted that comparisons between the breast and prostate cell line gene profiling data with dasatinib yielded a relatively small subset of shared genes, with only one (EphA2) shared in the limited gene set predictive model (19). Finally, although dasatinib and bosutinib share Src/Abl as a target, they have different chemical structures and inhibitory activity against the various Src family members (32,33).…”

Section: Discussionmentioning

confidence: 99%

“…One important preclinical study found a six-gene predictor for dasatinib susceptibility of breast cancer cell lines, and this was associated with a "triple-negative" [estrogen receptor (ER), progesterone receptor (PR), HER2] pattern in archival human breast cancer specimens (18). Another used a panel of prostate cancer cell lines to identify a five-gene set predictor, several of which were down-regulated after dasatinib treatment (19). We used a panel of 15 human tumor xenografts to explore the antitumor activity and search for pharmacodynamic and pharmacodiagnostic markers of efficacy to bosutinib in pancreas cancer.…”

Section: Introductionmentioning

confidence: 99%

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

Messersmith

Rajeshkumar

Tan

et al. 2009

Molecular Cancer Therapeutics

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Recently, Src tyrosine kinase has emerged as an attractive target for anticancer therapy, and Src is overexpressed in pancreatic cancer. The purpose of the study was to investigate the in vivo efficacy and pharmacodynamic effects of bosutinib (SKI-606), a Src/Abl inhibitor, using a panel of human pancreatic tumor xenografts. Surgically resected human pancreatic tumors were implanted into female nude mice and randomized to bosutinib versus control. Src and other pathways were analyzed by Western Blot, IHC, and Affymetrix U133 Plus 2.0 gene arrays. Of 15 patient tumors, 3 patient tumors were found to be sensitive to bosutinib, defined as tumor growth of <45% than that of control tumors. There were no definite differences between sensitive and resistant tumors in the baseline Src kinase pathway protein expression assessed by Western Blot. Caveolin-1 expression, as assessed by reverse transcription-PCR and immunohistochemistry, was frequently higher in sensitive cases. In sensitive tumors, bosutinib resulted in increased apoptosis. Phosphorylation of key signaling molecules downstream of Src, signal transducers and activators of transcription 3, and signal transducers and activators of transcription 3, were significantly inhibited by bosutinib. K-Top Scoring Pairs analysis of gene arrays gave a six-gene classifier that predicted resistance versus sensitivity in six validation cases. These results may aid the clinical development of bosutinib and other Src inhibitors in pancreas cancer.

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“…Dasatinib (Sprycel) is a novel, orally available, multitargeted, potent tyrosine kinase inhibitor that inhibits several critical oncogenic proteins, including BCR-ABL, SRC family kinases, c-KIT, PDGFR and ephrin A receptor kinase (Lombardo et al, 2004;Lee et al, 2005;Nam et al, 2005;Schittenhelm et al, 2006;Wang et al, 2007). Dasatinib has the greatest potency among the second-and third-generation tyrosine kinase inhibitors in vitro against ABL kinase activity (O' Hare et al, 2005;Quintas-Cardama et al, 2006), being 325-fold more potent than imatinib and 16-fold more potent than Therapeutic strategies for MPD C Kumar et al nilotinib.…”

Section: Ph( þ ) Mpd: CMLmentioning

confidence: 99%