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

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. doi: 10.18632/oncotarget.6122.
Masako Harada 1 2,  Juliana Benito 3,  Shinichi Yamamoto 2,  Surinder Kaur 4,  Dirim Arslan 4,  Santiago Ramirez 3,  Rodrigo Jacamo 3,  Leonidas Platanias 4,  Hiromichi Matsushita 5,  Tsutomu Fujimura 6 7,  Saiko Kazuno 6,  Kensuke Kojima 8,  Yoko Tabe 2 3,  Marina Konopleva 3
Affiliations

Affiliations

  • 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.
PMID: 26473447 DOI: 10.18632/oncotarget.6122
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.

Keywords

PIM inhibitor; acute myeloid leukemia (AML); heat shock factor (HSF); mTORC1/2 dual inhibitor.

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