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

K R Kampen1, A Ter Elst1, H Mahmud1

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

Leukemia
|November 19, 2013
PubMed

Insights

Targeting MEK in mixed lineage leukemia (MLL)-rearranged acute myeloid leukemia (AML) effectively reduced cancer cell survival. Combining MEK with VEGFR-2 inhibition further enhanced efficacy by simultaneously blocking key cancer pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Single kinase-targeted therapies often lead to limited responses in cancer due to bypass mechanisms.
  • Mixed lineage leukemia (MLL)-rearranged acute myeloid leukemia (AML) presents a challenge for targeted treatment strategies.

Purpose of the Study:

  • To identify druggable targets in MLL-rearranged AML using kinomic and proteomic profiling.
  • To evaluate the efficacy of targeting the mitogen-activated protein kinase (MAPK) pathway, specifically MEK inhibitors, in MLL-rearranged AML.
  • To investigate resistance mechanisms and explore combination therapies.

Main Methods:

  • High-throughput kinomic and proteomic approaches to identify aberrant activity profiles.
  • Pharmacological inhibition of MAPK pathway targets (MEK, CREB, JNK) in primary MLL-rearranged AML cells.
  • Proteomic analysis to explore the mechanism of MEK inhibition and resistance.
  • Assessment of combined MEK and VEGFR-2 inhibition.

Main Results:

  • MEK inhibition significantly decreased MLL-rearranged AML cell survival with no observed cytotoxicity in normal cells.
  • Inhibition of CREB and JNK did not show MLL selectivity.
  • MEK inhibition led to decreased Erk phosphorylation but sustained Akt/mTOR phosphorylation, allowing partial survival.
  • AML cells recovered through increased VEGFR-2 and Erk activity upon MEK inhibition exhaustion.
  • Combined MEK and VEGFR-2 inhibition demonstrated enhanced reduction in AML cell survival by simultaneously blocking Akt/mTOR and MAPK pathways.

Conclusions:

  • MEK is a promising druggable target in MLL-rearranged AML.
  • Understanding cancer cells' alternative escape routes is crucial for designing effective combination therapies.
  • Combined MEK and VEGFR-2 inhibition represents a rational and potentially effective therapeutic strategy for MLL-rearranged AML.

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