Intrinsic resistance to PIM kinase inhibition in AML through p38α-mediated feedback activation of mTOR signaling

// Diede Brunen 1 , Maria Jose Garcia-Barchino 2 , Disha Malani 3,* , Noorjahan Jagalur Basheer 4,* , Cor Lieftink 1 , Roderick L. Beijersbergen 1 , Astrid Murumagi 3 , Kimmo Porkka 5 , Maija Wolf 3 , C. Michel Zwaan 4 , Maarten Fornerod 4 , Olli Kallioniemi 3 , Jose Angel Martinez-Climent 2 and Rene Bernards 1 1 Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands 2 Division of Oncology, University of Navarra, Pamplona, Spain 3 Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland 4 Department of Pediatric Oncology, Erasmus Medical Center/Sophia Children’s Hospital, Rotterdam, The Netherlands ­5 Hematology Research Unit Helsinki, Department of Medicine, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland * These authors have contributed equally to this work Correspondence to: Rene Bernards, email: // Keywords : AML, PIM, AZD1208, p38, resistance Received : April 06, 2016 Accepted : May 23, 2016 Published : June 05, 2016 Abstract Although conventional therapies for acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL) are effective in inducing remission, many patients relapse upon treatment. Hence, there is an urgent need for novel therapies. PIM kinases are often overexpressed in AML and DLBCL and are therefore an attractive therapeutic target. However, in vitro experiments have demonstrated that intrinsic resistance to PIM inhibition is common. It is therefore likely that only a minority of patients will benefit from single agent PIM inhibitor treatment. In this study, we performed an shRNA-based genetic screen to identify kinases whose suppression is synergistic with PIM inhibition. Here, we report that suppression of p38α (MAPK14) is synthetic lethal with the PIM kinase inhibitor AZD1208. PIM inhibition elevates reactive oxygen species (ROS) levels, which subsequently activates p38α and downstream AKT/mTOR signaling. We found that p38α inhibitors sensitize hematological tumor cell lines to AZD1208 treatment in vitro and in vivo . These results were validated in ex vivo patient-derived AML cells. Our findings provide mechanistic and translational evidence supporting the rationale to test a combination of p38α and PIM inhibitors in clinical trials for AML and DLBCL.