Protein profiling identifies mTOR pathway modulation and cytostatic effects of Pim kinase inhibitor, AZD1208, in acute myeloid leukemia

• Published in: Leukemia & lymphoma Vol. 57; no. 12; pp. 2863 - 2873
• Main Authors: Chen, Lisa S., Yang, Ji-Yeon, Liang, Han, Cortes, Jorge E., Gandhi, Varsha
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.12.2016
• Subjects: AML; Apoptosis - drug effects; Biphenyl Compounds - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; growth inhibition; Humans; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; mTOR; Pim kinase; Protein Kinase Inhibitors - pharmacology; protein translation; Proteome; Proteomics - methods; Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors; Signal Transduction - drug effects; Thiazolidines - pharmacology; TOR Serine-Threonine Kinases - metabolism; Tumor Cells, Cultured; AML; mTOR; Pim kinase; protein translation; growth inhibition
• ISSN: 1042-8194; 1029-2403
• DOI: 10.3109/10428194.2016.1166489

Pim kinases phosphorylate and regulate a number of key acute myeloid leukemia (AML) cell survival proteins, and Pim inhibitors have recently entered clinical trial for hematological malignancies. AZD1208 is a small molecule pan-Pim kinase inhibitor and AZD1208 treatment resulted in growth inhibition and cell size reduction in AML cell lines including FLT3-WT (OCI-AML-3, KG-1a, and MOLM-16) and FLT3-ITD mutated (MOLM-13 and MV-4-11). There was limited apoptosis induction (<10% increase) in the AML cell lines evaluated with up to 3 μM AZD1208 for 24 h, suggesting that growth inhibition is not through apoptosis induction. Using reverse phase protein array (RPPA) and immunoblot analysis, we identified that AZD1208 resulted in suppression of mTOR signaling, including inhibition of protein phosphorylation of mTOR (Ser2448), p70S6K (Thr389), S6 (Ser235/236), and 4E-BP1 (Ser65). Consistent with mTOR inhibition, there was also a reduction in protein synthesis that correlated with cell size reduction and growth inhibition with AZD1208; our study provides insights into the mechanism of AZD1208.