Oncotarget

Research Papers:

LEE011 and ruxolitinib: a synergistic drug combination for natural killer/T-cell lymphoma (NKTCL)

Yan Ting Hee, Junli Yan, Dean Nizetic and Wee-Joo Chng _

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Oncotarget. 2018; 9:31832-31841. https://doi.org/10.18632/oncotarget.25835

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Abstract

Yan Ting Hee1,*, Junli Yan2,*, Dean Nizetic1,3 and Wee-Joo Chng2,4,5

1Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore

2Cancer Science Institute of Singapore, National University of Singapore, Singapore

3The Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK

4Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore

5Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

*These authors have contributed equally to this work

Correspondence to:

Wee-Joo Chng, email: [email protected]

Keywords: NKTCL; LEE011; ruxolitinib; drug combination; lymphoma

Received: December 28, 2017    Accepted: July 12, 2018    Published: August 07, 2018

ABSTRACT

Natural killer/T-cell lymphoma (NKTCL) is an aggressive non-Hodgkin lymphoma that has been facing limited success with conventional treatments, urging for the discovery of alternative strategies. Recent studies including ours have revealed that EZH2 and JAK-STAT signalling pathways are key contributors to NKTCL pathogenesis. In particular, we found that EZH2 is overexpressed and directly transcriptionally activates the CCND1 gene to confer growth advantage. CCND1 codes for cyclin D1, which complexes with CDK4/6 to promote G1 to S phase transition. Therefore in this study we investigated whether inhibiting both JAK1/2 and CDK4/6, using LEE011 and ruxolitinib respectively is effective in NKTL. We first demonstrate that separate LEE011 and ruxolitinib treatment is sufficient to cause growth inhibition of NKTCL cells. More importantly, we found that there is synergistic growth inhibitory effects on NKTCL cells with combination treatment of LEE011 and ruxolitinib. The results obtained shows that the targeting of both CDK4/6 and JAK1/2 are promising to develop better treatment alternatives for NKTCL.


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