Preclinical activity of CPI-0610, a novel small-molecule bromodomain and extra-terminal protein inhibitor in the therapy of multiple myeloma

Abstract

Inhibition of the bromodomain and extra-terminal (BET) proteins is a promising therapeutic strategy for various hematologic cancers. Previous studies suggest that BET inhibitors constrain tumor cell proliferation and survival mainly through the suppression of MYC transcription and activity. However, suppression of the transcription of additional genes also contributes to the antitumor activity of BET inhibitors but is less well understood. Here we examined the therapeutic potential of CPI-0610, a potent BET inhibitor currently undergoing phase I clinical testing, in multiple myeloma (MM). CPI-0610 displays potent cytotoxicity against MM cell lines and patient-derived MM cells through G cell cycle arrest and caspase-dependent apoptosis. CPI-0610-mediated BET inhibition overcomes the protective effects conferred by cytokines and bone marrow stromal cells. We also confirmed the in vivo efficacy of CPI-0610 in a MM xenograft mouse model. Our study found IKZF1 and IRF4 to be among the primary targets of CPI-0610, along with MYC. Given that immunomodulatory drugs (IMiDs) stabilize cereblon and facilitate Ikaros degradation in MM cells, we combined it with CPI-0610. Combination studies of CPI-0610 with IMiDs show in vitro synergism, in part due to concomitant suppression of IKZF1, IRF4 and MYC, providing a rationale for clinical testing of this drug combination in MM patients.

Replication Study: BET bromodomain inhibition as a therapeutic strategy to target c-Myc

“…Since that publication there have been additional studies examining the therapeutic strategy of targeting BET bromodomains in other types of cancer. This includes reports of antitumor effects using BET bromodomain inhibitors in MM(Chaidos et al, 2014 , Siu et al, 2016), ovarian cancer (Zhang et al, 2016), gastric cancer (Montenegro et al, 2014), childhood sarcoma (Bid et al, 2016), and triple negative breast cancer (da Motta et al, 2016; Shu et al, 2016). Acquired resistance to BET inhibitors have also been reported (Fong et al, 2015; Kumar et al, 2015; Rathert et al, 2015), with recent studies suggesting combinatorial drug treatment to overcome resistance mechanisms (Asangani et al, 2016; Kurimchak et al, 2016; Yao et al, 2015).…”

BET Proteins as Targets for Anticancer Treatment

“…Examples of key genes are MYC ( 4, 20, 22, 24 , 35-38, 43-47 ), AR and TMPRSS2 -ETS fusion genes ( 48,49 ), FOSL1 ( 50,51 ), E2F2 ( 38 ), ITK ( 31 ), IL7R ( 35,38,44,50 ), TERT ( 24,46 ), BCL2 ( 22,24,43,46 ), CDK6 ( 17,22,38,43 ), IRF4 ( 24,37,45 ), and IKZF1 ( 24,45 ). There are data indicating that the reduction in BRD4 binding is more marked at superenhancers and that their corresponding genes undergo stronger and faster downregulation than genes regulated by standard enhancers ( 1,17,37,52 ).…”

MYC—Master Regulator of the Cancer Epigenome and Transcriptome

“…However, despite the promise BETi show in MYC-positive cancers, these drugs have weak specificity as they downregulate hundreds of other genes, including genes not associated with super-enhancers. To be applicable in the clinic setting newly emerging molecules need to overcome the high cytotoxicity that the current generation of BETi displays in vivo [188,189]. Combination epigenetic therapy with BETi has shown promising synergistic effects, such as the cytotoxic activity of BETi, RVX2135, with the HDAC inhibitors SAHA or LBH-589 in MYC-induced lymphoma in mice [83].…”