Abstract
BackgroundInhibition 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).ResultsWe 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.ConclusionsWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-014-0034-6) contains supplementary material, which is available to authorized users.
Highlights
Inhibition of mitogen-activated protein kinase (MEK, known as MAPK2, MAPKK), a key molecule of the Ras/MAPK pathway, has shown promising effects on B-raf-mutated and some RAS-activated tumors in clinical trials
Fluorine-18-labeled glucose analog 2-fluoro-2deoxy-D-glucose-positron emission tomography ([18F] fluorine-18-labeled glucose analog 2-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET)) imaging has been used for monitoring neoadjuvant chemotherapy in patients with locally advanced breast cancer [5], non-small cell lung cancer [6], and lymphomas [7], for an early prediction of response to imatinib mesylate (GlivecTM) in patients with advanced soft tissue sarcoma [8] and in the evaluation of vemurafenib (ZelborafTM), an oral B-raf inhibitor [9]
Since RO4987655 is a selective mitogen-activated protein kinase kinase (MEK) inhibitor [25], it had no influence on pEGFR and pMEK at 6 h after the drug treatment, but, similar to pERK1/2, pMKK4, and cyclin D1, pEGFR and pMEK were up-regulated on day 3 (Figure 1b)
Summary
Inhibition of mitogen-activated protein kinase (MEK, 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. Non-invasive positron emission tomography (PET) imaging with the fluorine-18 labeled glucose analog 2-fluoro-2-deoxy-D-glucose ([18F] FDG) is being used as a functional endpoint in phase I to III clinical trials in oncology for assessing therapeutic response, in addition to conventional endpoints such as toxicity in tumor size. Fluorine-18-labeled glucose analog 2-fluoro-2deoxy-D-glucose-positron emission tomography ([18F] FDG-PET) imaging has been used for monitoring neoadjuvant chemotherapy in patients with locally advanced breast cancer [5], non-small cell lung cancer [6], and lymphomas [7], for an early prediction of response to imatinib mesylate (GlivecTM) in patients with advanced soft tissue sarcoma [8] and in the evaluation of vemurafenib (ZelborafTM), an oral B-raf inhibitor [9]. Several recent phase I doseescalation clinical trials have included [18F] FDGPET, for instance in assessing MEK inhibition as a monotherapy or in combination with other drugs in patients with advanced solid tumors [10,11,12]
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