This was not confirmed by a microarray analysis, suggesting either variability in tumors or technical differences in tumor dissection and mRNA detection. Expression of both tumor-derived and wild-type MCV LT in BJ fibroblasts induces survivin expression unless the Rbbinding motif is mutated. Both transcript and protein levels of survivin decrease upon T antigen knockdown in several MCVpositive MCC cell lines, and knockdown of survivin results in cell death. This has recently been confirmed by Xie et al. While LT induction of survivin may be required for MCVpositive MCC cell survival, additional signaling pathways are also likely to be targeted by MCV LT. A small molecule inhibitor of the survivin promoter, YM155, was initially identified using a promoter luciferase reporter assay. YM155 was able to diminish luciferase activity in a survivin promoter dependent context without cellular toxicity. YM155 has since been shown to bind interleukin enhancer binding factor 3, disrupting the ILF3/p54nrb transcriptional complex at the survivin promoter, decreasing E2F1/2-mediated transcriptional activation of survivin. YM155 antitumor activity has been demonstrated using a variety of cancer cell lines both in vitro and in mouse xenograft studies, and tested in phase I and II clinical trials for multiple malignancies. Exploiting the apparent dependence of BAY-60-7550 MCV-positive MCCs on survivin, YM155 was previously tested both in vitro and in vivo for MCC-specific cell killing with promising results. We show here that YM155 is a potent inhibitor of MCC progression for most, but not all, MCV-positive MCC Doxorubicin abmole xenografts in NSG mice. While YM155 is toxic to MCV-positive MCC cells in vitro, the combination of YM155 with other common chemotherapeutic agents results in additive, but not synergistic, killing of MCVpositive MCC cells. Despite prolonged suppression of MCC growth in responsive mice, most mice were ultimately euthanized due to progressive MCC disease during YM155 treatment. Our results suggest that survivin targeting by small molecule inhibitors may be a promising approach to MCC therapy. In this study we assessed the sensitivity of four MCV-positive MCCs to a small-molecule survivin inhibitor, YM155. Three of the four xenografts responded to YM155 treatment. YM155 efficacy is enhanced by extending the duration of treatment as well as by increasing YM155 dosage. However, the degree of YM155 efficacy is cell line dependent. MKL-1 is the most sensitive to YM155 both in vivo and in vitro, whereas MS-1 is the least sensitive to YM155 in vitro and does not respond to YM155 in vivo.