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, Marina Konopleva*

*Corresponding author for this work

Research output: Contribution to journalArticle

19 Scopus citations

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 AMPKa, 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.

Original languageEnglish (US)
Pages (from-to)37930-37947
Number of pages18
JournalOncotarget
Volume6
Issue number35
DOIs
StatePublished - 2015

Keywords

  • Acute myeloid leukemia (AML)
  • Heat shock factor (HSF)
  • PIM inhibitor
  • mTORC1/2 dual inhibitor

ASJC Scopus subject areas

  • Oncology

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    Harada, M., Benito, J., Yamamoto, S., Kaur, S., Arslan, D., Ramirez, S., Jacamo, R., Platanias, L., Matsushita, H., Fujimura, T., Kazuno, S., Kojima, K., Tabe, Y., & 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), 37930-37947. https://doi.org/10.18632/oncotarget.6122