TY - JOUR
T1 - Intrinsic resistance to PIM kinase inhibition in AML through p38α-mediated feedback activation of mTOR signaling
AU - Brunen, Diede
AU - García-Barchino, María José
AU - Malani, Disha
AU - Basheer, Noorjahan Jagalur
AU - Lieftink, Cor
AU - Beijersbergen, Roderick L.
AU - Murumägi, Astrid
AU - Porkka, Kimmo
AU - Wolf, Maija
AU - Michel Zwaan, C.
AU - Fornerod, Maarten
AU - Kallioniemi, Olli
AU - Martínez-Climent, José ángel
AU - Bernards, René
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - AML
KW - AZD1208
KW - P38
KW - PIM
KW - Resistance
UR - http://www.scopus.com/inward/record.url?scp=84978060447&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.9822
DO - 10.18632/oncotarget.9822
M3 - Article
C2 - 27270648
AN - SCOPUS:84978060447
SN - 1949-2553
VL - 7
SP - 37407
EP - 37419
JO - Oncotarget
JF - Oncotarget
IS - 25
ER -