β-Catenin Inhibitor BC2059 Is Efficacious as Monotherapy or in Combination with Proteasome Inhibitor Bortezomib in Multiple Myeloma.

摘要: Currently available treatment options are unlikely to be curative for the majority of multiple myeloma patients, emphasizing a continuing role introduction investigational agents that can overcome drug resistance. The canonical Wnt/β-catenin signaling pathway, essential self-renewal, growth, and survival, has been found dysregulated in myeloma, particularly advanced stages disease. This provides rationale evaluating novel β-catenin inhibitor BC2059 as monotherapy combination with proteasome inhibitors vitro vivo. Here, we show nuclear localization human cell lines (HMCL), consistent activation Wnt pathway. attenuates levels, both cytoplasm nucleus, reducing transcriptional activity TCF4/LEF complex expression its target gene axin 2. Treatment HMCL inhibits proliferation induces apoptosis dose-dependent manner. is also observed HMCL–stromal cocultures, mitigating protective effect afforded by stroma. Similarly, primary samples vitro, causing minimal on healthy peripheral blood mononuclear cells. Furthermore, it synergizes bortezomib samples. Finally, xenograft models myelomatosis, delays tumor growth prolongs survival minor on-target side effects. Collectively, these results demonstrate efficacy targeting pathway vivo, at clinically achievable doses. These findings support further clinical evaluation myeloma. Mol Cancer Ther; 16(9); 1765–78. ©2017 AACR.