Synergistic antitumor activity of lenalidomide with the BET bromodomain inhibitor CPI203 in bortezomib-resistant mantle cell lymphoma

Abstract

Bortezomib therapy has shown promising clinical activity in mantle cell lymphoma (MCL), but the development of resistance to proteasome inhibition may limit its efficacy. To unravel the factors involved in the acquisition of bortezomib resistance in vivo, immunodeficient mice were engrafted with a set of MCL cell lines with different levels of sensitivity to the drug, followed by gene expression profiling of the tumors and functional validation of the identified gene signatures. We observed an increased tumorigenicity of bortezomib-resistant MCL cells in vivo, which was associated with plasmacytic differentiation features, like interferon regulatory factor 4 (IRF4) and Blimp-1 upregulation. Lenalidomide was particularly active in this subgroup of tumors, targeting IRF4 expression and plasmacytic differentiation program, thus overcoming bortezomib resistance. Moreover, repression of the IRF4 target gene MYC in bortezomib-resistant cells by gene knockdown or treatment with CPI203, a BET (bromodomain and extra terminal) bromodomain inhibitor, synergistically induced cell death when combined with lenalidomide. In mice, addition of CPI203 to lenalidomide therapy further decreased tumor burden, involving simultaneous MYC and IRF4 downregulation and apoptosis induction. Together, these results suggest that exacerbated IRF4/MYC signaling is associated to bortezomib resistance in MCL in vivo and warrant clinical evaluation of lenalidomide plus BET inhibitor combination in MCL cases refractory to proteasome inhibition.

The BET Bromodomain Inhibitor OTX015 Affects Pathogenetic Pathways in Preclinical B-cell Tumor Models and Synergizes with Targeted Drugs

“…The mTOR is central to a signaling cascade leading to cell growth and proliferation, and mTOR inhibitors are approved for treatment of relapsed MCL (45). OTX015 was also synergistic with the PI3K-delta inhibitor idelalisib, which has shown promising clinical responses in B-cell lymphomas (46), and with the lenalidomide, as also recently reported for another BET bromodomain inhibitor in MCL (47).…”

Inhibition of bromodomain and extra-terminal proteins (BET) as a potential therapeutic approach in haematological malignancies: emerging preclinical and clinical evidence

“…CPI203 was shown to have a synergistic effect with lenalidomide in bortezomib-resistant mantle cell lymphoma (MCL), both in vitro in cell lines and in a xenograft model [Moros et al 2014]. Plasmacytic differentiation, driven by IRF4 overexpression, has been linked to bortezomib resistance in MCL [Perez-Galan et al 2011], while MYC is a direct IRF4 target in activated B cells and myeloma [Shaffer et al 2008].…”

“…CPI-203 is another benzodiazepine inhibitor structurally similar to JQ1, but with improved bioavailability profile in mice [King et al 2013]. It has shown preclinical evidence of efficacy in lymphomas [Ceribelli et al 2014;Moros et al 2014].…”

“…Plasmacytic differentiation, driven by IRF4 overexpression, has been linked to bortezomib resistance in MCL [Perez-Galan et al 2011], while MYC is a direct IRF4 target in activated B cells and myeloma [Shaffer et al 2008]. Combining CPI203 with lenalidomide inhibited transcriptional overexpression of IRF4 and MYC and overcame bortezomib resistance in vivo [Moros et al 2014].…”

IMiDs mobilize acute myeloid leukemia blasts to peripheral blood through downregulation of CXCR4 but fail to potentiate AraC/Idarubicin activity in preclinical models of non del5q/5q- AML

“…10,11 Some studies reported that lenalidomide has modest (pre)-clinical activity in lymphoma and AML with manageable toxicity. 9,12,13 Ongoing Phase I clinical trials assaying low- and high-dose lenalidomide for both newly diagnosed and relapsed/refractory AML also support that lenalidomide displays modest activity when given either alone or combined with cytarabine and anthracyclines. 14 …”