Phosphorylation of p70 Ribosomal Protein S6 Kinase β-1 is an Independent Prognostic Parameter in Metastatic Colorectal Cancer

Abstract

BackgroundDeregulation of signal transduction pathways plays a critical role in oncogenesis of colorectal cancer (CRC) and directly affects sensitivity to targeted therapies. Against this background we developed a comprehensive biomarker profiling program including markers of downstream signaling to study their association with clinical outcomes. Patients and MethodsA prospectively studied cohort of 160 patients with metastatic CRC was included. Standard diagnostic workup included mutational analyses of Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS), and v-Raf murine sarcoma viral oncogene homolog B (BRAF). In addition, markers of mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and mammalian target of rapamycin pathway activation (phosphorylation of extracellular signal-regulated kinase [ERK], AKT, and p70 ribosomal protein S6 kinase β-1 [p70S6K]) were studied using standardized immunohistochemistry. ResultsThere was a significant correlation between markers of ERK and AKT activation in the full cohort. In addition, phosphorylation of p70S6K correlated strongly with ERK and AKT phosphorylation and primary tumor localization in the right colon. Subgroup analyses specified these correlations to patients with all-RAS wild type tumors. In contrast, tumors harboring RAS mutations predominantly exhibited ERK phosphorylation. Interestingly, patients with CRC showing high p70S6K phosphorylation (highest quartile) had a significantly inferior overall survival (hazard ratio [HR], 2.4; P = .002) irrespective of RAS mutational status. This effect remained significant in multivariate analysis (P = .002). A patient subgroup characterized by high p70S6K phosphorylation and right-sided primary tumors had a particularly poor prognosis with a dramatically inferior overall survival (HR, 5.2; P < .001). Patients with right-sided primary tumor and low p70S6K phosphorylation had responses to anti-epidermal growth factor receptor antibody-based therapies and overall survival similar to patients with left-sided primary tumors. ConclusionHigh phosphorylation of p70S6K is a novel, independent biomarker for poor prognosis, in particular in patients with right-sided primary tumors.