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 GC-derived B-cell lymphomas.