The BET bromodomain inhibitor CPI203 improves lenalidomide and dexamethasone activity in in vitro and in vivo models of multiple myeloma by blockade of Ikaros and MYC signaling

Abstract

Most patients with multiple myeloma treated with current therapies, including immunomodulatory drugs, eventually develop relapsed/refractory disease. Clinical activity of lenalidomide relies on degradation of Ikaros and the consequent reduction in IRF4 expression, both required for myeloma cell survival and involved in the regulation of MYC transcription. Thus, we sought to determine the combinational effect of an MYC-interfering therapy with lenalidomide/dexamethasone. We analyzed the potential therapeutic effect of the combination of the BET bromodomain inhibitor CPI203 with the lenalidomide/dexamethasone regimen in myeloma cell lines. CPI203 exerted a dose-dependent cell growth inhibition in cell lines, indeed in lenalidomide/dexamethasone-resistant cells (median response at 0.5 μM: 65.4%), characterized by G1 cell cycle blockade and a concomitant inhibition of MYC and Ikaros signaling. These effects were potentiated by the addition of lenalidomide/dexamethasone. Results were validated in primary plasma cells from patients with multiple myeloma co-cultured with the mesenchymal stromal cell line stromaNKtert. Consistently, the drug combination evoked a 50% reduction in cell proliferation and correlated with basal Ikaros mRNA expression levels (P=0.04). Finally, in a SCID mouse xenotransplant model of myeloma, addition of CPI203 to lenalidomide/dexamethasone decreased tumor burden, evidenced by a lower glucose uptake and increase in the growth arrest marker GADD45B, with simultaneous downregulation of key transcription factors such as MYC, Ikaros and IRF4. Taken together, our data show that the combination of a BET bromodomain inhibitor with a lenalidomide-based regimen may represent a therapeutic approach to improve the response in relapsed/refractory patients with multiple myeloma, even in cases with suboptimal prior response to immunomodulatory drugs.

Enhanced expression of FCER1G predicts positive prognosis in multiple myeloma

“…MYC activation is associated with hyperdiploid MM and shorter survival, and also plays a causal role in the progression of monoclonal gammopathy to multiple myeloma. MYC protein overexpression is a feature of progression and adverse prognosis in multiple myeloma [42][43][44][45]. In recent research, it was also proved that sialyltransferase inhibition leads to inhibition of tumor cell interactions with VCAM1, and improves survival in a human multiple myeloma mouse model [46].…”

IRF4 Mediates the Oncogenic Effects of STAT3 in Anaplastic Large Cell Lymphomas

“…Interestingly, the possibility of combinatorial block of MYC and IRF4 gene expression was greatly advanced by the demonstration that treatment of multiple myeloma tumor cells with the BET-bromodomain inhibitor JQ1 led to loss of BRD4 at super-enhancers, and consequent transcription elongation defects of genes with super-enhancers, including MYC and IFR4 [ 62 ]. Indeed, numerous studies have demonstrated, both in vitro and in vivo, the synergistic antitumor activity of IMiDs and BET-bromodomain inhibitors [ 63 , 64 , 65 , 66 ]. We observed that the combination of pomalidomide with the BET family antagonist JQ1 has additive effects in four of five pomalidomide-insensitive cell lines.…”

Epigenetic‐Based Mechanisms of Osteoblast Suppression in Multiple Myeloma Bone Disease

“…The anti‐MM effects of BET inhibitors result from their inducing cell growth arrest and caspase‐mediated apoptosis by downregulation of c‐MYC transcription and concurrent genomewide downregulation of c‐myc target genes in MM cells . The BRD inhibitor CPI203 overcame melphalan and bortezomib resistance of MM cells in vitro, and in combination treatments, CPI203 synergized with bortezomib and melphalan as well as lenalidomide and dexamethasone regimens to induce apoptosis of MM cell lines . Although none of these studies measured the effects of BRD inhibitors on development of MM bone lesions, Diaz and colleagues tested the effectiveness of the BRD inhibitor CPI203 on primary patient CD138+ MM cell survival in cocultures with BMSCs.…”

“…The BRD inhibitor CPI203 overcame melphalan and bortezomib resistance of MM cells in vitro, and in combination treatments, CPI203 synergized with bortezomib and melphalan as well as lenalidomide and dexamethasone regimens to induce apoptosis of MM cell lines . Although none of these studies measured the effects of BRD inhibitors on development of MM bone lesions, Diaz and colleagues tested the effectiveness of the BRD inhibitor CPI203 on primary patient CD138+ MM cell survival in cocultures with BMSCs. In these experiments, CPI203 prevented BMSC‐mediated protection from the cytotoxic effects of the drug as well as the increased proliferation of MM cells usually found in BMSC cocultures.…”