Oncotarget

Research Papers:

Targeting protein kinase CK2 and CDK4/6 pathways with a multi-kinase inhibitor ON108110 suppresses pro-survival signaling and growth in mantle cell lymphoma and T-acute lymphoblastic leukemia

Amol Padgaonkar, Olga Rechkoblit, Rodgrigo Vasquez-Del Carpio, Venkat Pallela, Venkata Subbaiah DRC, Stephen C. Cosenza, Stacey J. Baker, M.V. Ramana Reddy, Aneel Aggarwal and Premkumar E. Reddy _

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Oncotarget. 2018; 9:37753-37765. https://doi.org/10.18632/oncotarget.26514

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Abstract

Amol Padgaonkar1,3, Olga Rechkoblit2, Rodgrigo Vasquez-Del Carpio1,4, Venkat Pallela5, Venkata Subbaiah DRC1,6, Stephen C. Cosenza1, Stacey J. Baker1, M.V. Ramana Reddy1, Aneel Aggarwal2 and E. Premkumar Reddy1,2

1Department of Oncological Sciences, Icahn School of Medicine, New York 10029, NY, USA

2Department of Pharmacological Sciences, Icahn School of Medicine, New York 10029, NY, USA

3Present Address: Prescient Healthcare Group, Jersey City 07302, NJ, USA

4Present address: Sandoz, a Novartis Company, Miami 33126, FL, USA

5Present address: Pfizer, Collegeville 19426, PA, USA

6Present address: Carnegie Pharmaceuticals, Monmouth Junction 08852, NJ, USA

Correspondence to:

E. Premkumar Reddy, email: ep.reddy@mssm.edu

Keywords: mantle cell lumphoma; T-cell acute lymphoblastic leukemia; CDK4; CK2

Received: December 06, 2018    Accepted: December 13, 2018    Published: December 28, 2018

ABSTRACT

Overexpression and constitutive activation of CYCLIN D1 and Casein Kinase 2 are common features of many hematologic malignancies, including mantle cell lymphoma (MCL) and leukemias such as T-cell acute lymphoblastic leukemia (T-ALL). Although both CK2 and CDK4 inhibitors have shown promising results against these tumor types, none of these agents have achieved objective responses in the clinic as monotherapies. Because both proteins play key roles in these and other hematological malignancies, we have analyzed the therapeutic potential of ON108110, a novel dual specificity ATP-competitive inhibitor of protein kinase CK2 as well as CDK4/6 in MCL and T-ALL. We show that in cell growth inhibition assays, MCL and T-ALL cell lines exhibited increased sensitivity to ON108110 when compared to other tumor types. Treatment with ON108110 reduced the level of phosphorylated RB-family proteins. In addition, ON108110 treatment resulted in concentration dependent inhibition of PTEN phosphorylation and a concomitant decrease in PI3K-AKT signaling mediated by CK2. Accordingly, cells treated with ON108110 rapidly accumulated in the G0/G1 stage of the cell cycle as a function of increasing concentration followed by rapid onset of apoptosis. Together, these results indicate that dual inhibition of CK2 and CDK4/6 may be an efficient treatment of MCL and T-ALLs displaying upregulation of CK2/PI3K and CDK4 signaling pathways.


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