The bromodomain inhibitor OTX015 (MK-8628) exerts anti-tumor activity in triple-negative breast cancer models as single agent and in combination with everolimus

Abstract

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subgroup of breast tumors clinically defined by the lack of estrogen, progesterone and HER2 receptors, limiting the use of the targeted therapies employed in other breast malignancies. Recent evidence indicates that c-MYC is a key driver of TNBC. The BET-bromodomain inhibitor OTX015 (MK-8628) has potent antiproliferative activity accompanied by c-MYC down-regulation in several tumor types, and has demonstrated synergism with the mTOR inhibitor everolimus in different models. The aim of this study was to evaluate the anti-tumor activity of OTX015 as single agent and in combination with everolimus in TNBC models. OTX015 was assayed in three human TNBC-derived cell lines, HCC1937, MDA-MB-231 and MDA-MB-468, all showing antiproliferative activity after 72 h (GI50 = 75–650 nM). This was accompanied by cell cycle arrest and decreased expression of cancer stem cells markers. However, c-MYC protein and mRNA levels were only down-regulated in MDA-MB-468 cells. Gene set enrichment analysis showed up-regulation of genes involved in epigenetic control of transcription, chromatin and the cell cycle, and down-regulation of stemness-related genes. In vitro, combination with everolimus was additive in HCC1937 and MDA-MB-231 cells, but antagonistic in MDA-MB-468 cells. In MDA-MB-231 murine xenografts, tumor mass was significantly (p < 0.05) reduced by OTX015 with respect to vehicle-treated animals (best T/C = 40.7%). Although everolimus alone was not active, the combination was more effective than OTX015 alone (best T/C = 20.7%). This work supports current clinical trials with OTX015 in TNBC (NCT02259114).

Nanoparticles Loaded with the BET Inhibitor JQ1 Block the Growth of Triple Negative Breast Cancer Cells In Vitro and In Vivo

“…A novel and promising approach is based on the use of compounds able to target the epigenome of breast cancer cells. In particular, among the molecules that inhibit the transcription of growth-promoting genes by acting on the "readers" of the acetylated histone marks, the bromo-and extra-terminal domain (BET) inhibitor JQ1 ((S)-tertbutyl2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno(3,2-f) (1,2,4)triazolo(4,3-a) (1,4)diazepin-6-yl)acetate) has shown a strong anti-proliferative action against TNBC cell lines and xenografts [4][5][6][7]. JQ1 acts by competing with acetylated histone residues, thus removing BET proteins from their chromatin targets.…”

A Chemical Toolbox for the Study of Bromodomains and Epigenetic Signaling

“…Unfortunately, selectivity and potency of tool compounds are often insufficient resulting in contradictory and erroneous results 19–22 . Following the disclosure of potent BET BRD inhibitors, other members of the BRD-family of interaction modules have been found to be highly druggable 23 , resulting in the identification of chemical fragments that were subsequently developed into potent and selective chemical probes 24–31 . However, BRDs outside the BET family have not been found to be major regulators of primary transcription control, posing challenges for the discovery of functional roles of these conserved domains 32 .…”

Chemoprevention of Preclinical Breast and Lung Cancer with the Bromodomain Inhibitor I-BET 762

“…Bromodomains are an attractive target for cancer therapeutics and have been intensively studied as treatment in many cancer types (47). Several studies reported the antiproliferative effects of bromodomain inhibitors in breast cancer cell lines and a reduction of tumor mass in mouse xenograft models (48)(49)(50). Arrested tumor growth by bromodomain inhibitors has also been shown in preclinical models of lung cancer.…”