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