Mammalian target of rapamycin (mTOR) inhibition activates phosphatidylinositol 3-kinase/Akt by up-regulating insulin-like growth factor-1 receptor signaling in acute myeloid leukemia: rationale for therapeutic inhibition of both pathways

• Published in: Blood Vol. 111; no. 1; pp. 379 - 382
• Main Authors: Tamburini, Jerome, Chapuis, Nicolas, Bardet, Valérie, Park, Sophie, Sujobert, Pierre, Willems, Lise, Ifrah, Norbert, Dreyfus, François, Mayeux, Patrick, Lacombe, Catherine, Bouscary, Didier
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01-01-2008; The Americain Society of Hematology
• Subjects: Biological and medical sciences; Cell Division - drug effects; Everolimus; Hematologic and hematopoietic diseases; Humans; Immunosuppressive Agents - pharmacology; In Vitro Techniques; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - metabolism; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Mechanistic Target of Rapamycin Complex 1; Medical sciences; Multiprotein Complexes; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation - drug effects; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Receptor, IGF Type 1 - metabolism; Signal Transduction - drug effects; Sirolimus - analogs & derivatives; Sirolimus - pharmacology; TOR Serine-Threonine Kinases; Transcription Factors - antagonists & inhibitors; Transcription Factors - metabolism; Up-Regulation - drug effects; Protein kinase mTOR; Acute myelogenous leukemia; Hematology; Enzyme; Transferases; Akt protein kinase; Malignant hemopathy; Insulin like growth factor 1; 1-Phosphatidylinositol 3-kinase; Treatment; Signaling pathway; Inhibitor; Cancer
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2007-03-080796

The phosphatidylinositol 3-kinase (PI3K)/Akt and mTORC1 pathways are frequently activated, representing potential therapeutic targets in acute myeloid leukemia (AML). In 19 AML samples with constitutive PI3K/Akt activation, the rapamycin derivative inhibitor everolimus (RAD001) increased Akt phosphorylation. This mTOR C1-mediated Akt up-regulation was explained by an insulin-like growth factor-1 (IGF-1)/IGF-1 receptor autocrine loop: (1) blast cells expressed functional IGF-1 receptors, and IGF-1-induced Akt activation was increased by RAD001, (2) a neutralizing anti-IGF-1R α-IR3 monoclonal antibody reversed the RAD001-induced Akt phosphorylation, and (3) autocrine production of IGF-1 was detected in purified blast cells by quantitative reverse transcription-polymerase chain reaction and immunofluorescence. This RAD001-induced PI3K/Akt up-regulation was due to an up-regulated expression of the IRS2 adaptor. Finally, we observed that concomitant inhibition of mTORC1 and PI3K/Akt by RAD001 and IC87114 induced additive antiproliferative effects. Our results suggest that dual inhibition of the mTORC1 complex and the IGF-1/IGF-1R/PI3K/Akt pathway in AML may enhance the efficacy of mTOR inhibitors in treatment of this disease.