Translational Medicine

ERK1/2 activation as a tractable biomarker during clinical evaluation of BRAF inhibitors and other inhibitors of the ERK1/2 pathway

BRAF, a serine–threonine kinase A, is a notable example of a protein activated through somatic mutation in cancer. Activating mutations in BRAF were identified by a systematic search of candidate cancer genes in a panel of diverse cancers; BRAF was then shown to be mutated in about two thirds of malignant melanomas. Because of the limited treatment options for metastatic malignant melanoma, the discovery of BRAF mutations triggered multiple drug-discovery programs in the academic and pharmaceutical sectors. BRAF mutations occur in malignant melanomas (27%-70%), papillary thyroid (36%-53%), colorectal (5%-22%), and serous ovarian cancer (~30%). Significantly, one of these mutations, the valine 600 to glutamate mutation (V600E) accounts for approximately 90% of the mutations identified. The V600EBRAF is ~500-fold more catalytically active than the wild-type protein, resulting in increased downstream signaling to ERK1/2, increased proliferation, oncogenic transformation, and tumor formation in animals. Depletion of V600EBRAF using small interfering RNA blocks ERK1/2 activation and proliferation and induces apoptosis. Because of the correlation between BRAF mutation status and ERK1/2 activation, ERK1/2 activation is frequently used as a biomarker during clinical evaluation of BRAF inhibitors and other inhibitors of the ERK1/2 pathway.

At QPS, the BRAF V600E mutation was determined using the Pyrosequencing technology platform. This technology provides a high throughput sequencing analysis to detect the BRAF 1799 T>A genetic polymorphism in patient's genomic DNA, which accounts for the V600E variant genotype. Based on the BRAF genotype, selected patient population may be recruited to improve the clinical outcome and a personalized treatment regimen may be designed. In addition, the ERK1/2 activation can be assessed by the measurements of total versus phosphorylated ERK1/2 in the patient's PBMC samples upon drug stimulation by a 2-plex ECL assay. Together the genetic polymorphism analysis and protein biomarker assessment allow us to get a better insight into the clinical evaluation of new anti-cancer drugs.

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Preliminary results from phase 1 clinical trials of small molecule inhibitors of the ERK1/2 pathway have shown extraordinary activity and further trials are in progress to show that such molecules will represent a novel class of anti-cancer drugs.

  • Multi-Parameter Cell Phenotyping
    • Extracellular and/or intracellular
    • Cell population/subpopulation percentages
  • Inflammatory Responses
  • Cell Viability
  • DNA Cell Content
  • Cell Cycle Analysis
  • Cytotoxicity Studies
  • Receptor Occupancy studies
  • Platelet Analysis
  • Cytometric Bead Array (CBA): Bead-based immunoassays of multiplexed biomarkers in individual samples (plasma or other biological matrix)

Combined with our strong biomarker, pharmacogenomics, and cell-based assay development capabilities, QPS’ new flow cytometry service offerings can provide excellent support for both research and clinical studies, particularly in the oncology and anti-inflammatory therapeutic areas.

For inquiries, please contact:

Susan Zondlo, Ph.D. at susan.zondlo@qps-usa.com, or LingSing Chen, Ph.D. at lingsing.chen@qps-usa.com.

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