Oncotarget

Research Papers:

Pim kinase inhibition sensitizes FLT3-ITD acute myeloid leukemia cells to topoisomerase 2 inhibitors through increased DNA damage and oxidative stress

Kshama A. Doshi, Rossana Trotta, Karthika Natarajan, Feyruz V. Rassool, Adriana E. Tron, Dennis Huszar, Danilo Perrotti and Maria R. Baer _

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Oncotarget. 2016; 7:48280-48295. https://doi.org/10.18632/oncotarget.10209

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Abstract

Kshama A. Doshi1,2, Rossana Trotta1,3, Karthika Natarajan1,2, Feyruz V. Rassool1,4, Adriana E. Tron5, Dennis Huszar5,#, Danilo Perrotti1,2, Maria R. Baer1,2,6

1University of Maryland Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA

2Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

3Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA

4Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA

5Oncology iMED, AstraZeneca, Waltham, MA, USA

6Veterans Affairs Medical Center, Baltimore, MD, USA

#Present address: Oncology Drug Discovery Unit, Takeda Pharmaceuticals International Co., Cambridge, MA, USA

Correspondence to:

Maria R. Baer, email: [email protected]

Keywords: acute myeloid leukemia, FLT3-ITD, Pim kinase, chemotherapy, reactive oxygen species

Received: May 15, 2016    Accepted: June 09, 2016    Published: June 21, 2016

ABSTRACT

Internal tandem duplication of fms-like tyrosine kinase-3 (FLT3-ITD) is frequent (30 percent) in acute myeloid leukemia (AML), and is associated with short disease-free survival following chemotherapy. The serine threonine kinase Pim-1 is a pro-survival oncogene transcriptionally upregulated by FLT3-ITD that also promotes its signaling in a positive feedback loop. Thus inhibiting Pim-1 represents an attractive approach in targeting FLT3-ITD cells. Indeed, co-treatment with the pan-Pim kinase inhibitor AZD1208 or expression of a kinase-dead Pim-1 mutant sensitized FLT3-ITD cell lines to apoptosis triggered by chemotherapy drugs including the topoisomerase 2 inhibitors daunorubicin, etoposide and mitoxantrone, but not the nucleoside analog cytarabine. AZD1208 sensitized primary AML cells with FLT3-ITD to topoisomerase 2 inhibitors, but did not sensitize AML cells with wild-type FLT3 or remission bone marrow cells, supporting a favorable therapeutic index. Mechanistically, the enhanced apoptosis observed with AZD1208 and topoisomerase 2 inhibitor combination treatment was associated with increased DNA double-strand breaks and increased levels of reactive oxygen species (ROS), and co-treatment with the ROS scavenger N-acetyl cysteine rescued FLT3-ITD cells from AZD1208 sensitization to topoisomerase 2 inhibitors. Our data support testing of Pim kinase inhibitors with topoisomerase 2 inhibitors, but not with cytarabine, to improve treatment outcomes in AML with FLT3-ITD.


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