PI3K/AKT Inhibitor BEZ-235 targets CCND2 and induces G1 Arrest in Breast Implant-Associated Anaplastic Large Cell Lymphoma

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an anaplastic lymphoma kinase-negative (ALKneg) T-cell lymphoma. In contrast to ALK-positive (ALKpos) ALCL, BIA-ALCL cells express cyclin D2 (CCND2), regulator of cyclin dependent kinases 4 and 6 (CDK4/6). The CDK4/6 inhibitor palbociclib effected dephosphorylation of the retinoblastoma protein (RB) and caused cell cycle arrest of BIA-ALCL tumor cell lines in G1. The PI3K/AKT inhibitor BEZ-235 induced dephosphorylation of the mTORC1 target S6 and of GSK3-beta, indicators for translational inhibition and proteasomal degradation. Consequently, CCND2 protein levels declined after stimulation with BEZ-235, RB was dephosphorylated and the cell cycle was arrested in G1. The CCND2 promoter is methylated in CCND2neg ALKpos ALCL cell lines, and unmethylated in CCND2pos BIA-ALCL cell lines implying a regulatory function of DNA methylation for the gene´s expression. If our cell lines data can be translated to primary tumor cells, CDK4/6 inhibitors and PI3K/AKT inhibitors might find application in the therapy for BIA-ALCL.