Modulation of plasma metabolite biomarkers of MAPK pathway with the MEK inhibitor RO4987655: pharmacodynamic and predictive potential in metastatic melanoma.
de Haven Brandon, A
de Bono, JS
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<p>MAPK pathway activation is frequently observed in human malignancies, including melanoma, and is associated with sensitivity to MEK inhibition and changes in cellular metabolism. Using quantitative mass spectrometry-based metabolomics, we identified in preclinical models 21 plasma metabolites including amino acids, propionylcarnitine, phosphatidylcholines and sphingomyelins that were significantly altered in two B-RAF mutant melanoma xenografts and that were reversed following a single dose of the potent and selective MEK inhibitor RO4987655. Treatment of non-tumour bearing animals and mice bearing the PTEN null U87MG human glioblastoma xenograft elicited plasma changes only in amino acids and propionylcarnitine. In patients with advanced melanoma treated with RO4987655, on-treatment changes of amino acids were observed in patients with disease progression and not in responders. In contrast, changes in phosphatidylcholines and sphingomyelins were observed in responders. Furthermore, pre-treatment levels of 7 lipids identified in the preclinical screen were statistically significantly able to predict objective responses to RO4987655. The RO4987655 treatment-related changes were greater than baseline physiological variability in non-treated individuals. This study provides evidence of a translational exo-metabolomic plasma readout predictive of clinical efficacy together with pharmacodynamic utility following treatment with a signal transduction inhibitor.
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Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicine (Banerji Drug Evaluation PD Group)
Prostate Cancer Targeted Therapy Group
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Mol Cancer Ther, 2017