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Acute Leukemias

Insights in dynamic kinome reprogramming as a consequence of MEK inhibition in MLL-rearranged AML

Leukemia volume 28, pages 589–599 (2014)Cite this article

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Abstract

Single kinase-targeted cancer therapies often failed prolonged responses because cancer cells bypass through alternative routes. In this study, high-throughput kinomic and proteomic approaches enabled to identify aberrant activity profiles in mixed lineage leukemia (MLL)-rearranged acute myeloid leukemia (AML) that defined druggable targets. This approach revealed impaired activity of proteins belonging to the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathway. Pharmacological druggable MAPK pathway targets tested in primary MLL-rearranged AML included MAPKK1/2 (MEK), cyclic AMP-responsive element-binding protein (CREB) and MAPK8/9 (JNK). MEK inhibition showed to severely decrease MLL-rearranged AML cell survival without showing cytotoxicity in normal controls, whereas inhibition of CREB and JNK failed to exhibit MLL selectivity. Exploring the working mechanism of MEK inhibition, we assessed proteome activity in response to MEK inhibition in THP-1. MAPK1/3 (Erk) phosphorylation was instantly decreased in concurrence with a sustained Akt/mammalian target of rapamycin (mTOR) phosphorylation that enabled a subpopulation of cells to survive MEK inhibition. After exhaustion of MEK inhibition the AML cells recovered via increased activity of vascular endothelial growth factor receptor-2 (VEGFR-2) and Erk proteins to resume their proliferative state. Combined MEK and VEGFR-2 inhibition strengthened the reduction in MLL-rearranged AML cell survival by blocking the Akt/mTOR and MAPK pathways simultaneously. The generation of insights in cancerous altered activity profiles and alternative escape mechanisms upon targeted therapy allows the rational design of novel combination strategies.

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Acknowledgements

RAS pathway mutations were obtained from MWJ Fornerod, MM van den Heuvel-Eibrink and CM Zwaan from the Department of Pediatric Oncology/Hematology, Erasmus MC—Sophia Children’s Hospital, Rotterdam, Netherlands. We thank Imclone for their generous supply of VEGFR-2 antibody IMC1121b. We also thank the patients who donated leukemia specimens and also physician assistants, nurse practitioners and fellows who acquired specimens. KRK was supported by a grant from the Foundation for Pediatric Oncology Groningen, The Netherlands (SKOG). The kinome data collection was supported by a grant from the Foundation KiKa, Amstelveen (AtE, HM and ESJMdB).

Author Contributions

KRK performed research, collected data, analyzed data and wrote the paper. AtE performed peptide array and background subtraction. HM performed statistical testing of peptide array results. SHD guided performing the peptide arrays. FJGS performed research and collected data. VdH contributed samples. MPP designed peptide arrays. VG performed quantile normalization and supervised peptide array analysis. ESJMdB designed research, analyzed data, supervised and wrote the paper.

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Authors and Affiliations

  1. Department of Pediatric Oncology/Hematology, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    K R Kampen, A ter Elst, H Mahmud, F J G Scherpen, S H Diks & E S J M de Bont

  2. Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands

    M P Peppelenbosch

  3. Dutch Childhood Oncology Group, Erasmus University College, Hague, The Netherlands

    V de Haas

  4. European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    V Guryev

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  1. K R Kampen
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Correspondence to E S J M de Bont.

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Kampen, K., ter Elst, A., Mahmud, H. et al. Insights in dynamic kinome reprogramming as a consequence of MEK inhibition in MLL-rearranged AML. Leukemia 28, 589–599 (2014). https://doi.org/10.1038/leu.2013.342

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