Targeting PLK-1 for Treating MYC-Driven Lymphomas
Abstract
We have previously shown that overexpression of Polo-like kinase (PLK)-1 is associated with poor clinical outcomes in patients with aggressive B cell lymphomas. We found that PLK-1 selective inhibitor, Volasertib, has a potent antitumor effect in aggressive B cell lymphomas in vitro and in vivo. Unfortunately, Volasertib was withdrawn in Phase III clinical trials due to its adverse effects probably related to myelosuppression. Herein, we developed a Volasertib antibody-drug conjugate (V-ADC) using CD19 antibody Inebilizumab in order to increase the targeting specificity for B-cell lymphoma cells and to minimize the side effects of Volasertib. However, our initial investigation found that V-ADC exhibited little cytotoxic effects, comparing to Volasertib treatment in Z138 cells, a mantle cell lymphoma cell line. CD19 has been known as a surface biomarker for normal and neoplastic B cell, however, we observed the level of CD19 expression in Z138 cells was relatively low. Furthermore, CD19 gene in Z138 carries a P. L174V mutation in exon 3 coding for extracellular domain. We thushypothesized that the ability of antigen recognition by Inebilizumab could be compromised by low level CD19 and/or CD19gene mutation. We thus established stable Z138 cell lines with overexpression of wild type CD19 (CD19-WT) and L174Vmutant CD19 (CD19-Mut) to further study the cytotoxic effect of V-ADC. We treated these cells with 10 nM V-ADC for 48 h andthe apoptotic subpopulations was determined by flow cytometry. We found that cells with CD19-overexpression, both wild type and mutant forms, exhibited markedly increased cell apoptosis comparing to parental cells (53-55% in overexpressing cells versus 5% in parental cells).
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2023
- Accession Number
- AD1216457
Entities
People
- Chengfeng Bi
- Chieko Saito
- Kai Fu
Organizations
- Roswell Park Comprehensive Cancer Center