Oncotarget

Research Papers:

The novel combination of dual mTOR inhibitor AZD2014 and pan-PIM inhibitor AZD1208 inhibits growth in acute myeloid leukemia via HSF pathway suppression

Masako Harada, Juliana Benito, Shinichi Yamamoto, Surinder Kaur, Dirim Arslan, Santiago Ramirez, Rodrigo Jacamo, Leonidas Platanias, Hiromichi Matsushita, Tsutomu Fujimura, Saiko Kazuno, Kensuke Kojima, Yoko Tabe and Marina Konopleva _

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Oncotarget. 2015; 6:37930-37947. https://doi.org/10.18632/oncotarget.6122

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Abstract

Masako Harada1,2,*, Juliana Benito3,*, Shinichi Yamamoto2, Surinder Kaur4, Dirim Arslan4, Santiago Ramirez3, Rodrigo Jacamo3, Leonidas Platanias4, Hiromichi Matsushita5, Tsutomu Fujimura6,7, Saiko Kazuno6, Kensuke Kojima8, Yoko Tabe2,3 and Marina Konopleva3

1 Research Institute for Environmental and Gender Specific Medicine, Juntendo University of Medicine, Tokyo, Japan

2 Department of Laboratory Medicine, Juntendo University of Medicine, Tokyo, Japan

3 Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

4 Division of Hematology-Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, Illinois, USA

5 Department of Laboratory Medicine, Tokai University School of Medicine, Kanagawa, Japan

6 BioMedical Research Center, Juntendo University of Medicine, Tokyo, Japan

7 Laboratory of Bioanalytical Chemistry, Tohoku Pharmaceutical University, Miyagi, Japan

8 Hematology, Respiratory Medicine and Oncology, Department of Medicine, Saga University, Saga, Japan

* These authors have contributed equally to this work

Correspondence to:

Marina Konopleva, email:

Keywords: acute myeloid leukemia (AML), mTORC1/2 dual inhibitor, PIM inhibitor, heat shock factor (HSF)

Received: May 06, 2015 Accepted: September 26, 2015 Published: October 14, 2015

Abstract

Mammalian target of rapamycin (mTOR) signaling is a critical pathway in the biology of acute myeloid leukemia (AML). Proviral integration site for moloney murine leukemia virus (PIM) serine/threonine kinase signaling takes part in various pathways exerting tumorigenic properties. We hypothesized that the combination of a PIM kinase inhibitor with an mTOR inhibitor might have complementary growth-inhibitory effects against AML. The simultaneous inhibition of the PIM kinase by pan-PIM inhibitor AZD1208 and of mTOR by selective mTORC1/2 dual inhibitor AZD2014 exerted anticancer properties in AML cell lines and in cells derived from primary AML samples with or without supportive stromal cell co-culture, leading to suppressed proliferation and increased apoptosis. The combination of AZD1208 and AZD2014 rapidly activated AMPKα, a negative regulator of translation machinery through mTORC1/2 signaling in AML cells; profoundly inhibited AKT and 4EBP1 activation; and suppressed polysome formation. Inhibition of both mTOR and PIM counteracted induction of heat-shock family proteins, uncovering the master negative regulation of heat shock factor 1 (HSF1), the dominant transcription factor controlling cellular stress responses. The novel combination of the dual mTOR inhibitor and pan-PIM inhibitor synergistically inhibited AML growth by effectively reducing protein synthesis through heat shock factor pathway suppression.


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