Abemaciclib, a CDK4/6 inhibitor, exerts preclinical activity against aggressive germinal center‐derived B‐cell lymphomas

Abstract

The revised WHO classification newly defined the entities "High-grade B-cell lymphoma with MYC and BCL2, and/or BCL6 rearrangements (HGBL-DH/TH)" and "HGBL, NOS." Standard immunochemotherapy for diffuse large B-cell lymphoma (DLBCL), R-CHOP, is insufficient for HGBL patients, and there are currently no optimized therapeutic regimens for HGBL. We previously reported that CCND3, which encodes cyclin D3, harbored high mutation rates in Burkitt lymphoma (BL), HGBL and a subset of DLBCL. Furthermore, the knockdown of cyclin D3 expression was toxic to germinal center (GC)-derived B-cell lymphomas. Thus, the fundamental function of cyclin D3 is important for the pathogenesis of GC-derived B-cell lymphoma. We herein used two structurally different CDK4/6 inhibitors, palbociclib and abemaciclib, and examined their suppressive effects on cell proliferation and their ability to induce apoptosis in various aggressive B-cell lymphoma cell lines. The results obtained demonstrated that abemaciclib more strongly suppressed cell proliferation and induced apoptosis in GC-derived B-cell lymphoma cell lines than the control, but only slightly inhibited those features in activated B-cell (ABC)-like DLBCL cell lines. Palbociclib exerted partial or incomplete effects compared with the control and the effect was intermediate between abemaciclib and the control. Moreover, the effects of abemaciclib appeared to depend on cyclin D3 expression levels based on the results of the expression analysis of primary aggressive B-cell lymphoma samples. Therefore, abemaciclib has potential as a therapeutic agent for aggressive GCderived B-cell lymphomas. K E Y W O R D S B-cell lymphoma, CDK4/6 inhibitor, cyclin D3, high-grade B-cell lymphoma, MYC

Abemaciclib, A Selective CDK4/6 Inhibitor, Restricts the Growth of Pediatric Ependymomas

“…Palbociclib was shown to effectively arrest cell cycle progression and tumor growth in several cancers, including hepatocellular carcinoma [25,26], glioblastoma [15,16,27], synovial sarcoma [28], medulloblastoma [19,29], AT/RTs [18], and gastric cancers [30]. Abemaciclib was also found to effectively induce cell cycle arrest and tumor growth inhibition in several cancers, including non-small cell lung cancer [22], glioblastoma [17], Ewing's sarcoma [31], multiple myeloma [32], and aggressive germinal center-derived B-cell lymphomas [33]. In this study, we demonstrated that abemaciclib treatment resulted in decreased expression of genes related to the cell cycle and DNA repair through inhibiting RB phosphorylation and total RB protein levels.…”

Cyclin-dependent kinase inhibitors exert distinct effects on patient-derived 2D and 3D glioblastoma cell culture models

“…While both agents induced autophagy with different intensities, abemaciclib additionally increased early apoptotic cells, while dinaciclib predominantly evoked necrosis. CDKi-mediated apoptosis has been described in various tumor models 19 – 23 . By contrast, autophagy was only recently described for abemaciclib 24 and just one publication described the cytoprotective role of autophagy under dinaciclib therapy in NSCLC 25 .…”

An Immune-Related Prognostic Classifier Is Associated with Diffuse Large B Cell Lymphoma Microenvironment

“…Cyclin-dependent kinase 4 (CDK4), a crucial player in cell cycle progression, is associated with DLBCL. The CDK4 inhibitor abemaciclib strongly suppresses cell proliferation and induces apoptosis in DLBCL [ 57 ]. The present results point to a strong positive correlation between CDK4 and the TFs KZF1 and NCAPG.…”