Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib

Abstract

Key Points• BA reduces MYC, CDK4/6, nuclear RelA, and BTK expression and is synergistically lethal with ibrutinib in MCL cells.• Cotreatment with BA and inhibitor of BCL2, CDK4/6, or histone deacetylases is synergistically lethal against ibrutinib-resistant MCL cells.Mantle cell lymphoma (MCL) cells exhibit increased B-cell receptor and nuclear factor (NF)-kB activities. The bromodomain and extra-terminal (BET) protein bromodomain 4 is essential for the transcriptional activity of NF-kB. Here, we demonstrate that treatment with the BET protein bromodomain antagonist (BA) JQ1 attenuates MYC and cyclindependent kinase (CDK)4/6, inhibits the nuclear RelA levels and the expression of NF-kB target genes, including Bruton tyrosine kinase (BTK) in MCL cells. Although lowering the levels of the antiapoptotic B-cell lymphoma (BCL)2 family proteins, BA treatment induces the proapoptotic protein BIM and exerts dose-dependent lethality against cultured and primary MCL cells. Cotreatment with BA and the BTK inhibitor ibrutinib 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 resistanceconferring BTK mutation. Cotreatment with BA and panobinostat (pan-histone deacetylase inhibitor) or palbociclib (CDK4/6 inhibitor) or synergistically induced apoptosis of the ibrutinib-resistant MCL cells. These findings highlight and support further in vivo evaluation of the efficacy of the BA-based combinations with these agents against MCL, including ibrutinib-resistant MCL. (Blood. 2015;126(13):1565-1574 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)-kB signaling genes. [1][2][3] These genetic alterations confer a cell autonomous pro-growth and pro-survival advantage on the MCL cells, which is especially dependent on NF-kB, BCL2, and MYC activities. [2][3][4] Next generation sequencing has also disclosed new targets for therapeutic intervention in the deregulated molecular signaling through BCR, toll-like receptor, NOTCH, NFkB, 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-kB 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....

Oncolytic Reactivation of KSHV as a Therapeutic Approach for Primary Effusion Lymphoma

“…Importantly, enrichment score was further increased in the combined treatment (NES 2.362) (Figure 6D). Consistent with previous studies, treatment with JQ1 also displayed significant enrichment of MYC target genes in both JQ1 alone (NES 1.485) and in combination with PEP005 (NES 1.730) (Figure S3C) (22,39). Again, combination further increased NES score of MYC target genes (Figure S3C).…”

“…Consistent with our in vitro observations that JQ1 did not possess strong cell killing capability (Figure 3A); the remaining viable PEL cells resumed growth as soon as the drug treatment was terminated. Similar results have been seen in other xenograft studies with JQ1 (22,39). Thus, the possible approach would be that administrating JQ1 to control tumor growth by targeting E2F and MYC (Figure 6D, Figure S3C), and providing specific cell killing effects by inducing KSHV reactivation and/or cytolytic drugs.…”

MYCL is a target of a BET bromodomain inhibitor, JQ1, on growth suppression efficacy in small cell lung cancer cells

“…However, the relative sensitivities to JQ1 were not associated with the expression of any of these genes in our panel of 14 SCLC cell lines. On the other hand, we identified CDK6 and BCL2 as JQ1 targets for transcriptional silencing in SCLC cells, as in leukemia [23, 36], lymphoma [37] and neuroblastoma [30]. In particular, the levels as well as reduction rates of CDK6 expression showed the strongest association with JQ1 sensitivity among the genes examined.…”

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

“…Sequential treatment with venetoclax and BTK inhibitors may also overcome impaired sensitivity to venetoclax resulting from CD40-mediated increase in BCL-X L expression, as demonstrated using MCL cell lines and peripheral MCL cells acquired from a patient undergoing ibrutinib treatment (72). Combination of the BET inhibitor JQ-1 with venetoclax synergistically induced apoptosis of ibrutinib-resistant MCL cell lines (73), perhaps suggesting another strategy to improve treatment options and outcomes for patients with MCL.…”