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The novel combination of dual mTOR inhibitor AZD2014 and pan-PIM inhibitor AZD1208 inhibits growth in acute myeloid leukemia via HSF pathway suppression.
Oncotarget 2015; 6(35):37930-47O

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.

Authors+Show Affiliations

Research Institute for Environmental and Gender Specific Medicine, Juntendo University of Medicine, Tokyo, Japan. Department of Laboratory Medicine, Juntendo University of Medicine, Tokyo, Japan.Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.Department of Laboratory Medicine, Juntendo University of Medicine, Tokyo, Japan.Division of Hematology-Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, Illinois, USA.Division of Hematology-Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, Illinois, USA.Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.Division of Hematology-Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, Illinois, USA.Department of Laboratory Medicine, Tokai University School of Medicine, Kanagawa, Japan.BioMedical Research Center, Juntendo University of Medicine, Tokyo, Japan. Laboratory of Bioanalytical Chemistry, Tohoku Pharmaceutical University, Miyagi, Japan.BioMedical Research Center, Juntendo University of Medicine, Tokyo, Japan.Hematology, Respiratory Medicine and Oncology, Department of Medicine, Saga University, Saga, Japan.Department of Laboratory Medicine, Juntendo University of Medicine, Tokyo, Japan. Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26473447

Citation

Harada, Masako, et al. "The Novel Combination of Dual mTOR Inhibitor AZD2014 and pan-PIM Inhibitor AZD1208 Inhibits Growth in Acute Myeloid Leukemia Via HSF Pathway Suppression." Oncotarget, vol. 6, no. 35, 2015, pp. 37930-47.
Harada M, Benito J, Yamamoto S, et al. The novel combination of dual mTOR inhibitor AZD2014 and pan-PIM inhibitor AZD1208 inhibits growth in acute myeloid leukemia via HSF pathway suppression. Oncotarget. 2015;6(35):37930-47.
Harada, M., Benito, J., Yamamoto, S., Kaur, S., Arslan, D., Ramirez, S., ... Konopleva, M. (2015). The novel combination of dual mTOR inhibitor AZD2014 and pan-PIM inhibitor AZD1208 inhibits growth in acute myeloid leukemia via HSF pathway suppression. Oncotarget, 6(35), pp. 37930-47. doi:10.18632/oncotarget.6122.
Harada M, et al. The Novel Combination of Dual mTOR Inhibitor AZD2014 and pan-PIM Inhibitor AZD1208 Inhibits Growth in Acute Myeloid Leukemia Via HSF Pathway Suppression. Oncotarget. 2015 Nov 10;6(35):37930-47. PubMed PMID: 26473447.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The novel combination of dual mTOR inhibitor AZD2014 and pan-PIM inhibitor AZD1208 inhibits growth in acute myeloid leukemia via HSF pathway suppression. AU - Harada,Masako, AU - Benito,Juliana, AU - Yamamoto,Shinichi, AU - Kaur,Surinder, AU - Arslan,Dirim, AU - Ramirez,Santiago, AU - Jacamo,Rodrigo, AU - Platanias,Leonidas, AU - Matsushita,Hiromichi, AU - Fujimura,Tsutomu, AU - Kazuno,Saiko, AU - Kojima,Kensuke, AU - Tabe,Yoko, AU - Konopleva,Marina, PY - 2015/05/06/received PY - 2015/09/26/accepted PY - 2015/10/17/entrez PY - 2015/10/17/pubmed PY - 2016/9/22/medline KW - PIM inhibitor KW - acute myeloid leukemia (AML) KW - heat shock factor (HSF) KW - mTORC1/2 dual inhibitor SP - 37930 EP - 47 JF - Oncotarget JO - Oncotarget VL - 6 IS - 35 N2 - 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. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/26473447/The_novel_combination_of_dual_mTOR_inhibitor_AZD2014_and_pan_PIM_inhibitor_AZD1208_inhibits_growth_in_acute_myeloid_leukemia_via_HSF_pathway_suppression_ L2 - http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=6122 DB - PRIME DP - Unbound Medicine ER -