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MEK1/2 inhibition decreases lactate in BRAF-driven human cancer cells

Maria Falck Miniotis1, Vaitha Arunan, Thomas R Eykyn

  • 1Cancer Research UK and EPSRC Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research, Sutton, Surrey, United Kingdom.

Cancer Research
|May 4, 2013
PubMed

Insights

MEK inhibitors reduce lactate levels in BRAF-driven cancers, offering a noninvasive biomarker for treatment response. Magnetic resonance spectroscopy (MRS) detects these metabolic changes, aiding targeted drug development.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The RAS/BRAF/MEK/ERK pathway is crucial in cancer development.
  • Targeted therapies like BRAF and MEK inhibitors are in clinical trials.
  • Noninvasive biomarkers are needed to assess early drug responses.

Purpose of the Study:

  • To investigate if MEK inhibitors reduce lactate levels, detectable by magnetic resonance spectroscopy (MRS).
  • To establish lactate as a metabolic biomarker for pharmacodynamic response to MEK inhibition.
  • To understand the metabolic effects of MEK inhibition in BRAF-driven cancers.

Main Methods:

  • Utilized MRS to monitor intracellular and extracellular lactate levels in cancer cells and melanoma tumors.
  • Employed (1)H MRS and a fluorescent glucose analog to assess glucose uptake.
  • Analyzed the impact of MEK1/2 signaling inhibition on lactate production and gene expression.

Main Results:

  • MEK1/2 inhibition decreased extracellular lactate in BRAF-dependent cells, but not BRAF-independent cells.
  • The reduction in lactate was time-dependent in BRAF-driven melanoma cells.
  • Observed decreased hexokinase-II expression, linked to c-Myc depletion, following MEK inhibition.

Conclusions:

  • MEK1/2 inhibition impacts cancer cell metabolism, particularly in BRAF-driven cancers.
  • MRS can serve as a noninvasive biomarker for pharmacodynamic response to MEK1/2 inhibitors.
  • Findings provide a preclinical basis for using MRS to monitor MEK inhibitor efficacy.

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