YM155 sensitizes triple‐negative breast cancer to membrane‐bound TRAIL through p38 MAPK‐ and CHOP‐mediated DR5 upregulation

• Published in: International journal of cancer Vol. 136; no. 2; pp. 299 - 309
• Main Authors: Pennati, Marzia, Sbarra, Stefania, De Cesare, Michelandrea, Lopergolo, Alessia, Locatelli, Silvia L., Campi, Elisa, Daidone, Maria Grazia, Carlo‐Stella, Carmelo, Gianni, Alessandro M., Zaffaroni, Nadia
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 15.01.2015
• Subjects: Adenoviruses; Animals; Apoptosis; Apoptosis - drug effects; Blotting, Western; Breast cancer; Cancer; Cell Membrane - metabolism; Cell Proliferation - drug effects; death receptors; Female; Flow Cytometry; Gene Expression Regulation, Neoplastic - drug effects; Humans; Imidazoles - pharmacology; Inhibitor of Apoptosis Proteins - antagonists & inhibitors; Inhibitor of Apoptosis Proteins - metabolism; Medical research; Mice; Mice, Inbred NOD; Mice, SCID; Naphthoquinones - pharmacology; p38 Mitogen-Activated Protein Kinases - metabolism; Reactive Oxygen Species - metabolism; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism; Rodents; survivin; TNF-Related Apoptosis-Inducing Ligand - metabolism; TRAIL; Transcription Factor CHOP - metabolism; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; triple‐negative breast cancer; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; YM155; survivin; triple-negative breast cancer; TRAIL; YM155; death receptors
• DOI: 10.1002/ijc.28993
• ISSN: 0020-7136

Because available treatments have limited efficacy in triple‐negative breast cancer (TNBC), the identification of new therapeutic strategies to improve patients' outcome is urgently needed. In our study, we investigated the effects of the administration of the small molecule selective survivin suppressant YM155, alone or in association with CD34+ cells transduced with a replication‐deficient adenovirus encoding the human tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) gene (CD34‐TRAIL+ cells), in three TNBC cell models. YM155 exposure significantly impaired TNBC cell growth and selectively modulated survivin expression at both mRNA and protein level. In addition, co‐culturing YM155‐treated TNBC cells with CD34‐TRAIL+ cells resulted in markedly increased cytotoxic effect and apoptotic response in comparison with single treatments. Such a chemosensitizing effect was observed only in TNBC cells inherently expressing DR5 and relied on the ability of YM155 to upregulate DR5 expression through a p38 MAPK‐ and CHOP‐dependent mechanism. YM155/CD34‐TRAIL+ combination also showed a significant inhibitory effect on the growth of DR5‐expressing TNBC cells following xenotransplantation into NOD/SCID mice, in the absence of toxicity. Overall, our data (i) provide, for the first time, evidence that YM155 sensitizes TNBC cells to CD34‐TRAIL+ cells‐induced apoptosis by a mechanism involving the downregulation of survivin and the simultaneous p38 MAPK‐ and CHOP‐mediated upregulation of DR5, and (ii) suggest the combination of YM155 with TRAIL‐armed CD34+ progenitor cells as a promising therapeutic option for patients with TNBC expressing DR5. What's new? In this study, a new combined treatment based on the use of the survivin inhibitor YM155 and CD34+ cells transduced with an adenovirus encoding the human TRAIL gene (CD34‐TRAIL+ cells) produced synergistic effects in experimental models of triple‐negative breast cancer (TNBC). Such antitumor effect relied on the ability of YM155 to up‐regulate the death receptor DR5 through a p38 MAPK‐ and CHOP‐dependent mechanism and was selectively observed in TNBC models inherently expressing DR5. The findings provide a molecular basis for a rational combination to be clinically exploited in TNBC and suggest DR5 expression as a possible marker for patient selection.