Intrinsic resistance to PIM kinase inhibition in AML through p38α-mediated feedback activation of mTOR signaling
Authors
Brunen, DiedeGarcía-Barchino, María José
Malani, Disha
Basheer, Noorjahan Jagalur
Lieftink, Cor
Beijersbergen, Roderick L.
Murumägi, Astrid
Porkka, Kimmo
Wolf, Maija
Zwaan, C. Michel
Fornerod, Maarten
Kallioniemi, Olli
Martínez-Climent, José Ángel
Bernards, René
Affiliation
Netherlands Cancer InstituteUniversity of Navarra
University of Helsinki
Erasmus Medical Center/Sophia Children’s Hospital
Helsinki University Central Hospital
Issue Date
2016-06-05
Metadata
Show full item recordAbstract
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.Citation
Brunen D, García-Barchino M, Malani D, Basheer N, Lieftink C, Beijersbergen R, Murumägi A, Porkka K, Wolf M, Zwaan CM, Fornerod M, Kallioniemi O, Martínez-Climent J, Bernards R (2016) 'Intrinsic resistance to PIM kinase inhibition in AML through p38α-mediated feedback activation of mTOR signaling', Oncotarget, 7 (25), pp.37407-37419.Publisher
Impact Journals LLCJournal
OncotargetPubMed ID
27270648PubMed Central ID
PMC5122321Additional Links
https://www.oncotarget.com/article/9822/text/Type
ArticleLanguage
enEISSN
1949-2553Sponsors
This study was supported (in part) by research funding from AstraZeneca to D.B. and R.B. This work was supported by grants from the Dutch Cancer Society, KIKA, KOCR Society Rotterdam, Academy of Finland Centre of Excellence, and Sigrid Juselius Foundation.ae974a485f413a2113503eed53cd6c53
10.18632/oncotarget.9822
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- Creative Commons
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International
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