Polo-like-kinase 1 (PLK-1) and c-myc inhibition with the dual kinase-bromodomain inhibitor volasertib in aggressive lymphomas
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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
Ryan A. Wilcox, email: [email protected]
Keywords: PLK-1; GATA-3; T-cell lymphoma; c-myc; volasertib
Received: September 07, 2017 Accepted: November 09, 2017 Published: December 06, 2017
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.
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