Modulation of Plasma Metabolite Biomarkers of the MAPK Pathway with MEK Inhibitor RO4987655: Pharmacodynamic and Predictive Potential in Metastatic Melanoma.
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Authors
Ang, JE
Pal, A
Asad, YJ
Henley, AT
Valenti, M
Box, G
de Haven Brandon, A
Revell, VL
Skene, DJ
Venturi, M
Rueger, R
Meresse, V
Eccles, SA
de Bono, JS
Kaye, SB
Workman, P
Banerji, U
Raynaud, FI
Pal, A
Asad, YJ
Henley, AT
Valenti, M
Box, G
de Haven Brandon, A
Revell, VL
Skene, DJ
Venturi, M
Rueger, R
Meresse, V
Eccles, SA
de Bono, JS
Kaye, SB
Workman, P
Banerji, U
Raynaud, FI
Document Type
Journal Article
Date
2017-10-01
Date Accepted
2017-06-06
Abstract
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-tumor-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, pretreatment levels of seven 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 nontreated 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. Mol Cancer Ther; 16(10); 2315-23. ©2017 AACR.
Citation
Molecular cancer therapeutics, 2017, 16 (10), pp. 2315 - 2323
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1535-7163
eISSN
1538-8514
Research Team
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Clinical Pharmacology – Adaptive Therapy
Medicine Drug Development Unit (de Bono)
Prostate Cancer Targeted Therapy Group
Medicine Drug Development Unit (Kaye)
Clinical Pharmacology – Adaptive Therapy
Medicine Drug Development Unit (de Bono)
Prostate Cancer Targeted Therapy Group
Medicine Drug Development Unit (Kaye)