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Tegnebratt T, Ruge E, Bader S, et al. Evaluation of efficacy of a new MEK inhibitor, RO4987655, in human tumor xenografts by [(18)F] FDG-PET imaging combined with proteomic approaches. EJNMMI Res. 2014;4(1):34doi: 10.1186/s13550-014-0034-6.
Tegnebratt, T., Ruge, E., Bader, S., Ishii, N., Aida, S., Yoshimura, Y., Ooi, C. H., Lu, L., Mitsios, N., Meresse, V., Mulder, J., Pawlak, M., Venturi, M., Tessier, J., & Stone-Elander, S. (2014). Evaluation of efficacy of a new MEK inhibitor, RO4987655, in human tumor xenografts by [(18)F] FDG-PET imaging combined with proteomic approaches. EJNMMI research, 4(1), 34. https://doi.org/10.1186/s13550-014-0034-6
Tegnebratt, Tetyana, et al. "Evaluation of efficacy of a new MEK inhibitor, RO4987655, in human tumor xenografts by [(18)F] FDG-PET imaging combined with proteomic approaches." EJNMMI research vol. 4,1 (2014): 34. doi: https://doi.org/10.1186/s13550-014-0034-6
Tegnebratt T, Ruge E, Bader S, Ishii N, Aida S, Yoshimura Y, Ooi CH, Lu L, Mitsios N, Meresse V, Mulder J, Pawlak M, Venturi M, Tessier J, Stone-Elander S. Evaluation of efficacy of a new MEK inhibitor, RO4987655, in human tumor xenografts by [(18)F] FDG-PET imaging combined with proteomic approaches. EJNMMI Res. 2014 Dec;4(1):34. doi: 10.1186/s13550-014-0034-6. Epub 2014 Sep 09. PMID: 26116108; PMCID: PMC4452660.
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EJNMMI Res. 2014 Dec;4(1):34. doi: 10.1186/s13550-014-0034-6. Epub 2014 Sep 09.

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

EJNMMI research

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

Affiliations

  1. Karolinska Institutet and Department of Neuroradiology, R3:00, MicroPET and Clinical Neurosciences, Karolinska University Hospital, Stockholm, 17176, Sweden, [email protected].

PMID: 26116108 PMCID: PMC4452660 DOI: 10.1186/s13550-014-0034-6

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 [(18)F] FDG-PET imaging and proteomics technology.

METHODS: [(18)F] 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 [(18)F] FDG uptake after MEK inhibition by RO4987655 as early as 2 h post-treatment. The greatest [(18)F] FDG decreases were found on day 1, followed by a rebound in [(18)F] 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 [(18)F] 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 [(18)F] 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 [(18)F] FDG-PET imaging and molecular proteomics. These results provide support for using preclinical [(18)F] 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 [(18)F] FDG-PET to optimize their clinical use.

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