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pmid26473447      Oncotarget 2015 ; 6 (35): 37930-47
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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 #MMPMID26473447
  • 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
  • Oncotarget 2015[Nov]; 6 (35): 37930-47 PMID26473447show ga
  • 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 AMPK?, 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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