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

Molecular Cancer Therapeutics
Ioanna SavvidouA Spencer

Abstract

Currently available treatment options are unlikely to be curative for the majority of multiple myeloma patients, emphasizing a continuing role for the introduction of investigational agents that can overcome drug resistance. The canonical Wnt/β-catenin signaling pathway, essential for self-renewal, growth, and survival, has been found to be dysregulated in multiple myeloma, particularly in advanced stages of disease. This provides the rationale for evaluating the novel β-catenin inhibitor BC2059 as monotherapy and in combination with proteasome inhibitors in vitro and in vivo Here, we show nuclear localization of β-catenin in human myeloma cell lines (HMCL), consistent with activation of the canonical Wnt pathway. BC2059 attenuates β-catenin levels, in both the cytoplasm and the nucleus, reducing the transcriptional activity of the TCF4/LEF complex and the expression of its target gene axin 2. Treatment of HMCL with BC2059 inhibits proliferation and induces apoptosis in a dose-dependent manner. This is also observed in HMCL-stromal cell cocultures, mitigating the protective effect afforded by the stroma. Similarly, BC2059 induces apoptosis in primary multiple myeloma samples in vitro, causing minimal apoptosis on healthy periph...Continue Reading

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Citations

Jun 26, 2018·International Journal of Molecular Sciences·Sridurga MithraprabhuAndrew Spencer
Feb 23, 2019·Journal of the National Cancer Institute·Motonari NomuraJason T Yustein
Mar 3, 2018·Blood·Steven Grant
Nov 14, 2019·Current Pharmaceutical Design·Morteza GhandadiSorour Ashari
Mar 14, 2020·British Journal of Haematology·Haiqin WangXiaojuan Xiao
Jul 19, 2020·International Journal of Molecular Sciences·Sabah AkhtarShahab Uddin
May 7, 2020·Frontiers in Genetics·Meral BeksacDilara Akcora Yildiz
May 20, 2018·Journal of Hematology & Oncology·Ingrid SpaanVictor Peperzak
Sep 28, 2020·Journal of Cancer Research and Clinical Oncology·Andrés Cardona-Echeverry, Jeanette Prada-Arismendy
Jan 8, 2021·Frontiers in Oncology·Michela Frenquelli, Giovanni Tonon
Mar 16, 2021·Current Oncology Reports·Ravin RatanAndrew J Bishop

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