Phospho-ERK levels as predictors for chemotherapy of rectal carcinoma.

Susanne Holck,Lars-Inge Larsson,Louise Laurberg Klarskov

doi:10.18632/oncotarget.26741

Abstract

Treatment of rectal cancer has been vastly improved by advances in surgery and radiochemotherapy but remains an important cause of morbidity and mortality worldwide. A particular problem is the lack of predictive markers that can help to individualize treatment. The growth- and apoptosis-regulating signaling molecules ERK 1 and 2 are important to cancer growth and progression. They are activated through phosphorylation, which is initiated by a cascade involving the EGF receptor and RAS as upstream regulators. Moreover, in vitro studies indicate that phospho-ERKs interfere with 5-fluorouracil-based chemotherapy. Recently, we showed that high levels of phospho-ERKs in rectal cancer cells predict poor responses to neoadjuvant (preoperative) radiochemotherapy. We now report that preoperative phospho-ERK levels also can subdivide high-risk rectal cancer patients into a favorable and a poor prognostic group with respect to recurrence-free survival. Importantly, phospho-ERK levels were of predictive significance only in high-risk patients, who received adjuvant (postoperative) chemotherapy, but not in high-risk patients not receiving such therapy. Our results suggest that high cancer cell levels of phospho-ERK predict poor responsiveness to both preoperative and postoperative chemotherapy of rectal cancer.

Highlights

Treatment of rectal cancer has been substantially improved by the introduction of total mesorectal excision surgery but the disease is still associated with considerable morbidity and mortality
extracellular signal-regulated kinase (ERK) activation proceeds through a cascade that is initiated by binding of EGF to cell surface receptors
The most important new finding of our study is that the cancer, but not stromal, phospho-ERK score, as determined on diagnostic biopsies, constitutes a significant predictor for recurrence-free survival (RFS) of locally advanced rectal adenocarcinomas (LARC) patients

Summary

Introduction

Treatment of rectal cancer has been substantially improved by the introduction of total mesorectal excision surgery but the disease is still associated with considerable morbidity and mortality. Adjuvant chemotherapy may be administered to high-risk patients. ERKs are activated by an array of upstream regulators, including the EGF receptor (EGFR), RAS, and RAF. Activating mutations in genes encoding these regulators are central to the development and/or progression of colorectal and other cancers [8,9,10]. ERK activation proceeds through a cascade that is initiated by binding of EGF (or other growth factors) to cell surface receptors. MEKs activate ERKs by dual phosphorylation to phospho-ERKs. Most phosphoERKs translocate to the nucleus, where they stimulate transcription of genes regulating cell cycle progression and apoptosis [6, 7, 10,11,12]. Of ERK-targeting MKPs, class I enzymes (MKP1/DUSP1, DUSP2/PAC-1, MKP-2/DUSP 4 and DUSP5)

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