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Targeted Polo-like Kinase Inhibition Combined With Aurora Kinase Inhibition in Pediatric Acute Leukemia Cells

Jayanthan, Aarthi PhD*,†; Hofmann, Bradley MBT*; Meier-Stephenson, Vanessa PhD*; Perinpanayagam, Maneka PhD*; Dunn, Sandra E. RN, PhD; Boklan, Jessica MD, PhD; Trippett, Tanya M. MD§; Truong, Tony H. MD*; Narendran, Aru MD, PhD*

Journal of Pediatric Hematology/Oncology: August 2019 - Volume 41 - Issue 6 - p e359–e370
doi: 10.1097/MPH.0000000000001416
Online Articles: Original Articles
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Background: Recent studies have shown that cell cycle events are tightly controlled by complex and shared activities of a select group of kinases. Among these, polo-like kinases (Plks) are regulatory mitotic proteins that are overexpressed in several types of cancer and are associated with poor prognosis.

Materials and Methods: We have evaluated, in preclinical in vitro studies, the activity of a panel of Plk inhibitors against cell lines derived from refractory pediatric leukemia, as well as primary leukemia cells, in culture. Through in vitro growth inhibition studies, Western blot analysis for the expression and activation of key regulators of cell growth and survival and gene silencing studies, we specifically examined the ability of these agents to induce cytotoxicity through the activation of apoptosis and their capacity to interact and modulate the expression and phosphorylation of Aurora kinases.

Results: Our findings show that the various Plk-1 inhibitors in development show potential utility for the treatment of pediatric leukemia and exhibit a wide range of phosphorylation and target modulatory capabilities. Finally, we provide evidence for a complex interregulatory relationship between Plk-1 and Aurora kinases enabling the identification of synergy and biologic correlates of drug combinations targeting the 2 distinct enzyme systems.

Discussion: This information provide the rationale for the evaluation of Plk-1 as an effective target for therapeutics in refractory pediatric leukemia and indicate compensatory activities between Plk-1 and Aurora kinases, providing insight into some of the complex mechanisms involved in the process of cell division.

*Division of Pediatric Oncology, Alberta Children’s Hospital, and POETIC Laboratory for Preclinical and Drug Discovery Studies, University of Calgary, Calgary, AB

Phoenix Molecular Designs, Vancouver, BC, Canada

Division of Hematology/Oncology, Childrens Center for Cancer and Blood Disorders, Phoenix Children’s Hospital, Phoenix, AZ

§Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY

Supported in part by the Alberta Children’s Hospital Foundation, Kids Cancer Care Foundation of Alberta and the POETIC Foundation.

The authors declare no conflict of interest.

Reprints: Aru Narendran, MD, PhD, Division of Pediatric Oncology, Alberta Children’s Hospital, 2888 Shaganappi Trail NW, Calgary, AB, Canada, T3B 6A8 (e-mail: a.narendran@ucalgary.ca).

Received September 24, 2018

Accepted December 8, 2018

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