Because it also depletes BTK expression, cotreatment with BA and ibrutinib may prevent the emergence of the mutant versions of BTK that confer resistance against ibrutinib administered alone in patients with MCL

Because it also depletes BTK expression, cotreatment with BA and ibrutinib may prevent the emergence of the mutant versions of BTK that confer resistance against ibrutinib administered alone in patients with MCL. JQ1 treatment attenuates the levels of the antiapoptotic proteins Bcl-xL, XIAP, MCL-1, BCL2, and em p /em -AKT, as well as upregulates the proapoptotic proteins p27 and BIM. synergistically induces apoptosis of MCL cells. Compared with each agent alone, cotreatment with BA and ibrutinib markedly improved the median survival of mice engrafted with the MCL cells. BA treatment also induced apoptosis of the in vitro isolated, ibrutinib-resistant MCL cells, which overexpress CDK6, BCL2, Bcl-xL, XIAP, and AKT, but lack ibrutinib resistance-conferring BTK mutation. Cotreatment Rabbit Polyclonal to NEK5 with BA and panobinostat (pan-histone deacetylase inhibitor) or palbociclib (CDK4/6 inhibitor) or ABT-199 (BCL2 antagonist) synergistically induced apoptosis of the ibrutinib-resistant MCL cells. These findings spotlight and support further in vivo evaluation of the efficacy of the BA-based combinations with these brokers against MCL, including ibrutinib-resistant MCL. Introduction Among the genetic alterations described in mantle cell lymphoma (MCL) cells are those that involve p53, cyclin-dependent kinase (CDK)4, CDKN2A, MYC, B-cell lymphoma (BCL)2, B-cell receptor (BCR), and nuclear factor (NF)-B signaling genes.1-3 These genetic alterations confer a cell autonomous pro-growth and pro-survival advantage around the MCL cells, which is especially dependent on NF-B, BCL2, and MYC activities.2-4 Next generation sequencing has also disclosed new targets for therapeutic intervention in the deregulated molecular signaling through BCR, toll-like receptor, NOTCH, NF-B, and mitogen-activated protein kinase signaling pathways in the MCL cell lines and patient-derived primary MCL.3-7 Pre-clinical and clinical studies have shown that ibrutinib, a selective, orally bioavailable, irreversible inhibitor of Bruton tyrosine kinase (BTK) in the BCR, also inhibits NF-B activity and is active against B-cell neoplasms, including chronic lymphocytic leukemia (CLL) and MCL.6,8 Ibrutinib has demonstrated impressive clinical efficacy and is approved for the treatment of CLL and MCL.9-11 Despite its high level of clinical activity, primary or acquired clinical resistance to ibrutinib therapy is commonly observed.11-14 Similar to what has been described in CLL cells, a cysteine-to-serine (C481S) mutation in BTK at the binding site of ibrutinib, which results in a protein that is only reversibly inhibited by ibrutinib, has also been documented (Rac)-Antineoplaston A10 in MCL patients who relapsed while on ibrutinib.12-14 However, none of these ibrutinib resistance-associated mutations were detectable in the primary pre-ibrutinib treatment MCL tumor samples.15 Instead, mutations (Rac)-Antineoplaston A10 in MLL2, CREBBP, PIM1, and ERB4 were detected in the ibrutinib-refractory MCL cells.13,15 Additionally, as compared with the cell lines sensitive to ibrutinib exhibiting chronic activity of the classical NF-B signaling pathway, ibrutinib-resistant MCL cell lines and primary MCL cells exhibited mutations in TRAF2/3 and MAP3K14 (NF-B inducing kinase), activating the alternative NF-B signaling, which would still show dependency (Rac)-Antineoplaston A10 around the NF-BCactivated transcriptome for growth and survival.7,16 The deregulated transcriptome in these cells would also be governed by the genetic alterations and epigenetic mechanisms that control the expressions of MYC, BCL2, and the G1 checkpoint proteins.3,7,16,17 Acetylation-deacetylation of the histone proteins regulates the transcriptome in transformed cells.18 The bromodomain and extra-terminal (BET) family of reader proteins, including bromodomain (BRD)2, BRD3, and BRD4 recognize and bind to the acetylated lysine residues around the histone proteins associated with the open, transcriptionally permissive chromatin through their amino-terminal double, tandem, 110 amino acids-long BRDs.19-21 BET proteins also contain the extra-terminal protein-interacting domain in the carboxyl (C) terminus, which assembles a complex of coregulatory proteins at the enhancers and promoters, thereby regulating gene transcription.20,21 The C-terminal positive transcription elongation factor b (pTEFb)-interacting domain of BRD4 interacts with and recruits the to the super-enhancers and promoters, thereby regulating the activity of RNA pol II (RNAP2) and gene expressions of important MCL-relevant oncogenes.21-24 Among these are MYC, CDK4/6, cyclin D1, and BCL-2, which control the proliferation and survival of MCL cells.22-24 pTEFb, which is a heterodimer composed of cyclin T and CDK9, phosphorylates Ser-2 around the heptad repeats of the C-terminal domain name (CTD) in the stalled RNAP2 at the transcriptional start sites, enabling the pause-release of RNAP2 and inducing productive messenger RNA (mRNA) transcript elongation.24-28 Thus, by promoting the availability of active pTEFb, BRD4 couples histone acetylation to transcript elongation, especially of the MCL-relevant oncogenes c-MYC, cyclin D1, BCL-2, and CDK6.21-24 BRD4 is also essential for the transcriptional activity of NF-B triggered by the BCR signaling.29,30 BRD4 has also been shown to bind to the acetylated RelA and mediate the transcriptional activity of NF-B.30 Several structure/activity-based BET protein bromodomain antagonists (BAs) have been.