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Br J Cancer. 2017 Aug 8;117(4):494-502. doi: 10.1038/bjc.2017.195. Epub 2017 Jun 29.

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

Author information

1
Center for Applied Proteomics and Molecular Medicine, George Mason University, 10920 George Mason Circle, Manassas, VA 20110, USA.
2
Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
3
Department of Obstetrics and Gynecology, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128 Roma, Italy.
4
Division of Gynecologic Oncology, 'Angelo Nocivelli' Institute of Molecular Medicine, University of Brescia, Piazzale Spedali Civili 1, 25123 Brescia, Italy.
5
The University of Arizona Cancer Center, 3838N Campbell Ave, Tucson, AZ 85719, USA.

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.

PMID:
28664915
PMCID:
PMC5558684
DOI:
10.1038/bjc.2017.195
[Indexed for MEDLINE]
Free PMC Article

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