Kinase-driven metabolic signalling as a predictor of response to carboplatin\u2013paclitaxel adjuvant treatment in advanced ovarian cancers

Abstract

Background:The biological mechanisms underlying early- and advanced-stage epithelial ovarian cancers (EOCs) are still poorly understood. This study explored kinase-driven metabolic signalling in early and advanced EOCs, and its role in tumour progression and response to carboplatin–paclitaxel treatment.Methods:Tumour epithelia were isolated from two independent sets of primary EOC (n=72 and 30 for the discovery and the validation sets, respectively) via laser capture microdissection. Reverse phase protein microarrays were used to broadly profile the kinase-driven metabolic signalling of EOC with particular emphasis on the LBK1–AMPK and AKT–mTOR axes. Signalling activation was compared between early and advanced lesions, and carboplatin–paclitaxel-sensitive and -resistant tumours.Results:Advanced EOCs were characterised by a heterogeneous kinase-driven metabolic signature and decreased phosphorylation of the AMPK–AKT–mTOR axis compared to early EOC (P<0.05 for AMPKα T172, AMPKα1 S485, AMPKβ1 S108, AKT S473 and T308, mTOR S2448, p70S6 S371, 4EBP1 S65, GSK-3 α/β S21/9, FOXO1 T24/FOXO3 T32, and FOXO1 S256). Advanced tumours with low relative activation of the metabolic signature and increased FOXO1 T24/FOXO3 T32 phosphorylation (P=0.041) were associated with carboplatin–paclitaxel resistance.Conclusions:If validated in a larger cohort of patients, the decreased AMPK–AKT–mTOR activation and phosphorylation of FOXO1 T24/FOXO3 T32 may help identify carboplatin–paclitaxel-resistant EOC patients.