Insights in dynamic kinome reprogramming as a consequence of MEK inhibition in MLL-rearranged AML.
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.
Department of Pediatric Oncology/Hematology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
K R
KR
Kampen
Department of Pediatric Oncology/Hematology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
A
A
Ter Elst
Department of Pediatric Oncology/Hematology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
H
H
Mahmud
Department of Pediatric Oncology/Hematology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
F J G
FJ
Scherpen
Department of Pediatric Oncology/Hematology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
S H
SH
Diks
Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands.
M P
MP
Peppelenbosch
Dutch Childhood Oncology Group, Erasmus University College, Hague, The Netherlands.
V
V
de Haas
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
V
V
Guryev
Department of Pediatric Oncology/Hematology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
E S J M
ES
de Bont
D045744:Cell Line, Tumor; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D010770:Phosphotransferases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
C497422:KMT2A protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D010770:Phosphotransferases; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020930:MAP Kinase Kinase Kinases