Journal
MOLECULAR CANCER THERAPEUTICS
Volume 16, Issue 10, Pages 2315-2323Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-16-0881
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Funding
- Cancer Research UK programme at the Cancer Research UK Cancer Therapeutics Unit [C309/A11566]
- Cancer Research UK [C309/A8992]
- Wellcome Trust as part of the Wellcome Trust PhD programme at Institute of Cancer Research [090952/Z/09/Z]
- Roche
- Drug Development Unit
- Royal Marsden NHS Foundation Trust
- Institute of Cancer Research
- Experimental Cancer Medicine Centre
- National Health Service
- Royal Marsden Hospital
- Wellcome Trust [090952/Z/09/Z] Funding Source: Wellcome Trust
- BBSRC [BB/I019405/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/I019405/1] Funding Source: researchfish
- Cancer Research UK [11566] Funding Source: researchfish
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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 trea-ted 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. (C) 2017 AACR.
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