Oncotarget

Research Papers:

Phospho-ERK1/2 levels in cancer cell nuclei predict responsiveness to radiochemotherapy of rectal adenocarcinoma

Susanne Holck, Hans Jørgen Nielsen, Niels Pedersen and Lars-Inge Larsson _

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Oncotarget. 2015; 6:34321-34328. https://doi.org/10.18632/oncotarget.5761

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Abstract

Susanne Holck1, Hans Jørgen Nielsen2, Niels Pedersen2 and Lars-Inge Larsson1,3

1 Department of Pathology, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark

2 Department of Surgical Gastroenterology, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark

3 Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark

Correspondence to:

Lars-Inge Larsson, email:

Keywords: ERK, radiochemotherapy, rectal carcinoma, immunohistochemistry, phosphorylation

Received: July 23, 2015 Accepted: September 05, 2015 Published: September 21, 2015

Abstract

Locally advanced rectal adenocarcinoma is treated with radiochemotherapy (RCT) before surgery. The response to RCT is heterogeneous and consensus regarding reliable predictors is lacking. Since the ERK pathway is implicated in radioprotection, we examined pretreatment biopsies from 52 patients by immunohistochemistry for phosphorylated ERK (pERK). Immunostaining for pERK was considerably enhanced by use of alkaline demasking. Nuclear staining occurred in both cancer cells and stromal cells. Blind-coded sections were scored by 2 independent investigators. In patients showing no residual tumor after RCT (TRG1), staining for pERK in cancer, but not stromal, cell nuclei was significantly weaker than in patients showing a poor RCT response (TRG1 vs TRG4: p = 0.0001). Nuclear staining for pERK predicted poor responders, as illustrated by receiver operating characteristic curves with an area under curve of 0.86 (p = 0.0007) and also predicted downstaging (area under curve: 0.76; p = 0.01). A number of controls documented the specificity of the optimized staining method and results were confirmed with another pERK antibody. Thus, staining for pERK in cancer cell nuclei can predict the response to RCT and may help spare poor responders this treatment. These results also raise the question whether inhibitors of ERK activation may serve as response modifiers of RCT.


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