Polo-Like Kinase 1: A Novel Target for the Treatment of Therapy-Resistant Mantle Cell Lymphoma

Abstract

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma (NHL) which is one of the most aggressive lymphomas. Despite recent improvements in therapies, the development of therapy-resistance is still a major problem; therefore, in order to understand the molecular basis of therapy-resistance, stable therapy-resistant MCL cell lines have been established by us. Based on the gene expression profiles of these cell lines, Polo-like kinase 1 (PLK1) was chosen as a therapeutic target. In this paper, we demonstrate a significant antilymphoma effect of targeting PLK1 in therapy-resistant MCL cells and primary MCL cells from refractory patients. PLK1 knockdown with the antisense oligonucleotide (ASO)/or small molecule inhibitor BI2536 showed significantly decreased proliferation and increased apoptosis in therapy-resistant MCL cell lines and MCL primary cells. Additionally, the direct proteinprotein interaction partners of PLK1 were mapped using ingenuity pathway and confirmed the level of association of these partners with PLK1 based on their expression changes following PLK1 knockdown using real-time PCR. Results suggest that PLK1 is a viable target for the treatment of therapy-resistant MCL.

Polo‐like kinase and its inhibitors: Ready for the match to start?

“…Using a subcutaneous tumor deposit model, combination therapy of BI 6727volasertib with either cytarabine or azacitidine showed reduced mean tumor volume growth when compared to single agent alone, without significant weight loss or other adverse signs being noted. Similar translational work has been replicated by other groups in many hematologic malignancies, including chronic myeloid leukemia , multiple myeloma , mantle cell lymphoma and diffuse large b‐cell lymphoma . These results taken together supported moving forward the clinical development of the class, especially in the case of AML in combination with other agents.…”

“…Preclincial work with Plk1 inhibition in the hematologic malignancies has demonstrated promising activity, with the majority of studies in acute leukemias . Using both patient samples and established AML cell lines, Renner et al established that Plk1 was highly expressed in many (14/22) patient samples as well as cell lines (5/6) but not non‐malignant CD34+ controls .…”