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Open Access 01-12-2014 | Original research

Evaluation of efficacy of a new MEK inhibitor, RO4987655, in human tumor xenografts by [¹⁸F] FDG-PET imaging combined with proteomic approaches

Authors: Tetyana Tegnebratt, Elisabeth Ruge, Sabine Bader, Nobuya Ishii, Satoshi Aida, Yasushi Yoshimura, Chia-Huey Ooi, Li Lu, Nicholas Mitsios, Valerie Meresse, Jan Mulder, Michael Pawlak, Miro Venturi, Jean Tessier, Sharon Stone-Elander

Published in: EJNMMI Research | Issue 1/2014

Abstract

Background

Inhibition of mitogen-activated protein kinase (MEK, also known as MAPK2, MAPKK), a key molecule of the Ras/MAPK (mitogen-activated protein kinase) pathway, has shown promising effects on B-raf-mutated and some RAS (rat sarcoma)-activated tumors in clinical trials. The objective of this study is to examine the efficacy of a novel allosteric MEK inhibitor RO4987655 in K-ras-mutated human tumor xenograft models using [¹⁸F] FDG-PET imaging and proteomics technology.

Methods

[¹⁸F] FDG uptake was studied in human lung carcinoma xenografts from day 0 to day 9 of RO4987655 therapy using microPET Focus 120 (CTI Concorde Microsystems, Knoxville, TN, USA). The expression levels of GLUT1 and hexokinase 1 were examined using semi-quantitative fluorescent immunohistochemistry (fIHC). The in vivo effects of RO4987655 on MAPK/PI3K pathway components were assessed by reverse phase protein arrays (RPPA).

Results

We have observed modest metabolic decreases in tumor [¹⁸F] FDG uptake after MEK inhibition by RO4987655 as early as 2 h post-treatment. The greatest [¹⁸F] FDG decreases were found on day 1, followed by a rebound in [¹⁸F] FDG uptake on day 3 in parallel with decreasing tumor volumes. Molecular analysis of the tumors by fIHC did not reveal statistically significant correlations of GLUT1 and hexokinase 1 expressions with the [¹⁸F] FDG changes. RPPA signaling response profiling revealed not only down-regulation of pERK1/2, pMKK4, and pmTOR on day 1 after RO4987655 treatment but also significant up-regulation of pMEK1/2, pMEK2, pC-RAF, and pAKT on day 3. The up-regulation of these markers is interpreted to be indicative of a reactivation of the MAPK and activation of the compensatory PI3K pathway, which can also explain the rebound in [¹⁸F] FDG uptake following MEK inhibition with RO4987655 in the K-ras-mutated human tumor xenografts.

Conclusions

We have performed the first preclinical evaluation of a new MEK inhibitor, RO4987655, using a combination of [¹⁸F] FDG-PET imaging and molecular proteomics. These results provide support for using preclinical [¹⁸F] FDG-PET imaging in early, non-invasive monitoring of the effects of MEK and perhaps other Ras/MAPK signaling pathway inhibitors, which should facilitate a wider implementation of clinical [¹⁸F] FDG-PET to optimize their clinical use.

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Title: Evaluation of efficacy of a new MEK inhibitor, RO4987655, in human tumor xenografts by [18F] FDG-PET imaging combined with proteomic approaches
Authors: Tetyana Tegnebratt
Elisabeth Ruge
Sabine Bader
Nobuya Ishii
Satoshi Aida
Yasushi Yoshimura
Chia-Huey Ooi
Li Lu
Nicholas Mitsios
Valerie Meresse
Jan Mulder
Michael Pawlak
Miro Venturi
Jean Tessier
Sharon Stone-Elander
Publication date: 01-12-2014
Publisher: Springer Berlin Heidelberg
Published in: EJNMMI Research / Issue 1/2014
Electronic ISSN: 2191-219X
DOI: https://doi.org/10.1186/s13550-014-0034-6

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Evaluation of efficacy of a new MEK inhibitor, RO4987655, in human tumor xenografts by [¹⁸F] FDG-PET imaging combined with proteomic approaches

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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