Survivin Is a Therapeutic Target in Merkel Cell Carcinoma

Abstract

Merkel cell polyomavirus (MCV) causes ~80% of primary and metastatic Merkel cell carcinomas (MCCs). By comparing digital transcriptome subtraction deep-sequencing profiles, we found that transcripts of the cellular survivin oncoprotein [BIRC5a (baculoviral inhibitor of apoptosis repeat-containing 5)] were up-regulated sevenfold in virus-positive compared to virus-negative MCC tumors. Knockdown of MCV large T antigen in MCV-positive MCC cell lines decreased survivin mRNA and protein expression. Exogenously expressed MCV large T antigen increased survivin protein expression in non-MCC primary cells. This required an intact retinoblastoma protein–targeting domain that activated survivin gene transcription as well as expression of other G1-S–phase proteins including E2F1 and cyclin E. Survivin expression is critical to the survival of MCV-positive MCC cells. A small-molecule survivin inhibitor, YM155, potently and selectively initiates irreversible, nonapoptotic, programmed MCV-positive MCC cell death. Of 1360 other chemotherapeutic and pharmacologically active compounds screened in vitro, only bortezomib (Velcade) was found to be similarly potent, but was not selective in killing MCV-positive MCC cells. YM155 halted the growth of MCV-positive MCC xenograft tumors and was nontoxic in mice, whereas bortezomib was not active in vivo and mice displayed serious morbidity. Xenograft tumors resumed growth once YM155 treatment was stopped, suggesting that YM155 may be cytostatic rather than cytotoxic in vivo. Identifying the cellular pathways, such as those involving survivin, that are targeted by tumor viruses can lead to rapid and rational identification of drug candidates for treating virus-induced cancers.

Therapeutic potential of sepantronium bromide YM155 in gemcitabine-resistant human urothelial carcinoma cells

“…Due to the increased ratio of G0/G1 phase without G1 arrest, YM155 induced G0 phase stasis, known as quiescence, was substantiated. Our results are consistent with those of Arora et al who demonstrated the early inhibition of DNA synthesis in Merkel cell carcinoma by YM155 (46). After 48-h YM155 treatment, the increased expression of p27 kip1 , a potent inhibitor of cyclin-CDK complex formation, supported this idea.…”

Age and Gender Associations of Virus Positivity in Merkel Cell Carcinoma Characterized Using a Novel RNA In Situ Hybridization Assay

“…Although reports on prognostic significance have been mixed regarding whether the presence of MCPyV detection is associated with improved outcome, a recent large prospective study of 282 cases using multimodal MCPyV detection with qPCR and IHC demonstrated significantly better outcome for MCPyV-positive tumors (28). In addition, the presence of MCPyV may influence tumor sensitivity to immunotherapy and targeted therapy (5,29,30). Hence, detection of MCPyV in MCC tumors has diagnostic and prognostic utility and may have a future role in guiding management.…”

Combined inhibition of Wee1 and Hsp90 activates intrinsic apoptosis in cancer cells

“…19,20 Survivin has been validated as a therapeutic target in cancer, and small molecules that inhibit Survivin transcription show activity in some preclinical cancer models, including prostate cancer. 21,22 However, initial clinical evaluation of the Survivin inhibitor YM155 reported only modest single-agent activity in patients with refractory, advanced non-small cell lung cancer, suggesting that combination with other chemotherapy or targeted agents may be clinically warranted. 23 In addition, more robust suppression of Survivin expression, perhaps as a consequence of targeting several pathways that impact Survivin, as we have shown here, may be beneficial.…”