Additive effect on survival of Raf kinase inhibitor protein and signal transducer and activator of transcription 3 in high‐grade glioma

Abstract

Animal studies have shown cooperative contribution of the Ras/Raf/MAPK and PI3K/Akt/mTOR signaling pathways in glioblastoma formation. However, this joint action has not yet been confirmed in human studies. The expression of Raf kinase inhibitory protein (RKIP) was examined in 159 patients with high-grade and low-grade gliomas and correlated with previously obtained data on the activation of signal transducer and activator of transcription 3 (STAT3), a downstream effector of the PI3K/Akt/mTOR signaling pathway. RKIP expression was associated with a longer overall survival in high-grade glioma cases without showing a direct or inverse correlation with tyrosine-705 phosphorylation of STAT3 (pSTAT3). Notably, RKIP-positive and pSTAT3 negative cases demarcate a patients group with exceptionally long survival, exceeding the prognostic impact of each single marker. The results of this study indicated that 1) RKIP expression correlates with tumor grade and is a marker for good prognosis in high-grade gliomas; 2) RKIP expression and lack of pSTAT3 have a cumulative prognostic impact; and 3) RKIP and pSTAT3 are likely to operate independently to influence survival. These findings represented the first human evidence of an additive effect of 2 distinct signaling pathways in high-grade glioma, suggesting that simultaneous inhibition of multiple pathways should be considered as a treatment strategy for these patients.