Oncotarget

Research Papers:

Polo-like-kinase 1 (PLK-1) and c-myc inhibition with the dual kinase-bromodomain inhibitor volasertib in aggressive lymphomas

Carlos Murga-Zamalloa, Avery Polk, Walter Hanel, Pinki Chowdhury, Noah Brown, Alexandra C. Hristov, Nathanael G. Bailey, Tianjiao Wang, Tycel Phillips, Sumana Devata, Pradeep Poonnen, Juan Gomez-Gelvez, Kedar V. Inamdar and Ryan A. Wilcox _

PDF  |  HTML  |  How to cite  |  Order a Reprint

Oncotarget. 2017; 8:114474-114480. https://doi.org/10.18632/oncotarget.22967

Metrics: PDF 513 views  |   HTML 1226 views  |   ?  


Abstract

Carlos Murga-Zamalloa1,2, Avery Polk1, Walter Hanel1, Pinki Chowdhury1, Noah Brown2, Alexandra C. Hristov2, Nathanael G. Bailey3, Tianjiao Wang1, Tycel Phillips1, Sumana Devata1, Pradeep Poonnen1, Juan Gomez-Gelvez4, Kedar V. Inamdar4 and Ryan A. Wilcox1

1Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA

2Department of Pathology, University of Michigan, Ann Arbor, MI, USA

3Division of Hematopathology, University of Pittsburgh, Pittsburgh, PA, USA

4Department of Pathology, Henry Ford Hospital, Detroit, MI, USA

Correspondence to:

Ryan A. Wilcox, email: rywilcox@med.umich.edu

Keywords: PLK-1; GATA-3; T-cell lymphoma; c-myc; volasertib

Received: September 07, 2017     Accepted: November 09, 2017     Published: December 06, 2017

ABSTRACT

Survival following anthracycline-based chemotherapy remains poor among patients with most T-cell lymphoproliferative disorders. This may be attributed, at least in part, to cell-autonomous mechanisms of chemotherapy resistance observed in these lymphomas, including the loss of important tumor suppressors and the activation of signaling cascades that culminate in the expression and activation of transcription factors promoting cell growth and survival. Therefore, the identification of novel therapeutic targets is needed. In an effort to identify novel tumor dependencies, we performed a loss-of-function screen targeting ≈500 kinases and identified polo-like kinase 1 (PLK-1). This kinase has been implicated in the molecular cross-talk with important oncogenes, including c-Myc, which is itself an attractive therapeutic target in subsets of T-cell lymphomas and in high-grade (“double hit”) diffuse large B-cell lymphomas. We demonstrate that PLK-1 expression is prevalent among these aggressive lymphomas and associated with c-myc expression. Importantly, PLK-1 inhibtion with the PLK-1 inhibitor volasertib significantly reduced downstream c-myc phosphorylation and impaired BRD4 binding to the c-myc gene, thus inhibiting c-myc transcription. Therefore, volasertib led to a nearly complete loss of c-myc expression in cell lines and tumor xenografts, induced apoptosis, and thus warrants further investigation in these aggressive lymphomas.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 22967