Intrinsic resistance to PIM kinase inhibition in AML through p38α-mediated feedback activation of mTOR signaling.
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.
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Diede
D
Brunen
Division of Oncology, University of Navarra, Pamplona, Spain.
María José
MJ
García-Barchino
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Disha
D
Malani
Department of Pediatric Oncology, Erasmus Medical Center/Sophia Children's Hospital, Rotterdam, The Netherlands.
Noorjahan
N
Jagalur Basheer
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Cor
C
Lieftink
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Roderick L
RL
Beijersbergen
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Astrid
A
Murumägi
Kimmo
K
Porkka
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Maija
M
Wolf
Department of Pediatric Oncology, Erasmus Medical Center/Sophia Children's Hospital, Rotterdam, The Netherlands.
C Michel
CM
Zwaan
Department of Pediatric Oncology, Erasmus Medical Center/Sophia Children's Hospital, Rotterdam, The Netherlands.
Maarten
M
Fornerod
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Olli
O
Kallioniemi
Division of Oncology, University of Navarra, Pamplona, Spain.
José Ángel
JÁ
Martínez-Climent
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
René
R
Bernards
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D047428:Protein Kinase Inhibitors; C546842:MTOR protein, human; D051573:Proto-Oncogene Proteins c-pim-1; D058570:TOR Serine-Threonine Kinases; C406031:proto-oncogene proteins pim; D048308:Mitogen-Activated Protein Kinase 14
AML; AZD1208; PIM; p38; resistance