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

Maria Isabella Sereni, Elisa Baldelli, Guido Gambara, Antonella Ravaggi, K. Alex Hodge, David S. Alberts, Jose M. Guillen-Rodriguez, Ting Dong, Maurizio Memo, Franco Odicino, Roberto Angioli, Lance A. Liotta, Sergio L. Pecorelli, Emanuel F. Petricoin, Mariaelena Pierobon

Research output: Contribution to journalArticle

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)494-502
Number of pages9
JournalBritish journal of cancer
Volume117
Issue number4
DOIs
StatePublished - Aug 8 2017

Keywords

  • chemo-sensitivity
  • kinase signalling
  • metabolism
  • ovarian cancer
  • reverse phase protein microarray

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Kinase-driven metabolic signalling as a predictor of response to carboplatin-paclitaxel adjuvant treatment in advanced ovarian cancers'. Together they form a unique fingerprint.

  • Cite this

    Sereni, M. I., Baldelli, E., Gambara, G., Ravaggi, A., Hodge, K. A., Alberts, D. S., Guillen-Rodriguez, J. M., Dong, T., Memo, M., Odicino, F., Angioli, R., Liotta, L. A., Pecorelli, S. L., Petricoin, E. F., & Pierobon, M. (2017). Kinase-driven metabolic signalling as a predictor of response to carboplatin-paclitaxel adjuvant treatment in advanced ovarian cancers. British journal of cancer, 117(4), 494-502. https://doi.org/10.1038/bjc.2017.195