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 peripheral blood mononuclear cells. Furthermore, it synergizes with the proteasome inhibitor bortezomib both in HMCL and primary multiple myeloma samples. Finally, in xenograft models of human myelomatosis, BC2059 delays tumor growth and prolongs survival with minor on-target side effects. Collectively, these results demonstrate the efficacy of targeting the Wnt/β-catenin pathway with BC2059 both in vitro and in vivo, at clinically achievable doses. These findings support further clinical evaluation of BC2059 for the treatment of multiple myeloma. Mol Cancer Ther; 16(9); 1765-78. ©2017 AACR.
Highlights
Multiple myeloma is an incurable neoplastic plasma cell disorder, accounting for approximately 1% of neoplastic diseases and 13% of hematologic cancers [1]
We demonstrated that BC2059 exposure reduced nuclear b-catenin protein levels in a dose- and time-dependent manner and impaired b-catenin/TCF transcriptional activity without any evidence of interference, based on the reduction in the overall cellular level of b-catenin, of b-catenin binding to its destruction complex
According to previously published data [16], the drug interferes with the interaction of b-catenin with TBL1–TBLR1, which are uniformly expressed in human myeloma cell lines (HMCL) (Supplementary Fig. S4) and which have a dual role of facilitating the transcriptional activity of the former [18], as well as protecting it from Siah-1–mediated degradation both in the nucleus and cytoplasm [20]
Summary
Multiple myeloma is an incurable neoplastic plasma cell disorder, accounting for approximately 1% of neoplastic diseases and 13% of hematologic cancers [1]. The canonical Wnt signaling pathway modulates the balance between stemness and differentiation in several adult stem cell niches, including hemopoiesis within the bone marrow [3]. It is commonly dysregulated in a range of solid tumors including colon, liver, and pancreas carcinoma [4] and hematologic malignancies, including acute myeloid leukemia [4, 5], chronic myeloid leukemia [6], chronic lymphocytic leukemia [7], and multiple myeloma [8]. B-catenin remains unphosphorylated, accumulates in the cytoplasm, and translocates into the nucleus, where it binds to the TCL/LEF complex initiating transcription of Wnt target genes [9]
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