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

3 Citations (Scopus)

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

Fingerprint

Carboplatin
Paclitaxel
Ovarian Neoplasms
Phosphotransferases
AMP-Activated Protein Kinases
Phosphorylation
Therapeutics
Neoplasms
Laser Capture Microdissection
Glycogen Synthase Kinase 3
Protein Array Analysis
Ovarian epithelial cancer
Epithelium

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Kinase-driven metabolic signalling as a predictor of response to carboplatin-paclitaxel adjuvant treatment in advanced ovarian cancers. / Sereni, Maria Isabella; Baldelli, Elisa; Gambara, Guido; Ravaggi, Antonella; Hodge, K. Alex; Alberts, David S; Guillen-Rodriguez, Jose M.; Dong, Ting; Memo, Maurizio; Odicino, Franco; Angioli, Roberto; Liotta, Lance A.; Pecorelli, Sergio L.; Petricoin, Emanuel F.; Pierobon, Mariaelena.

In: British Journal of Cancer, Vol. 117, No. 4, 08.08.2017, p. 494-502.

Research output: Contribution to journalArticle

Sereni, MI, Baldelli, E, Gambara, G, Ravaggi, A, Hodge, KA, Alberts, DS, Guillen-Rodriguez, JM, Dong, T, Memo, M, Odicino, F, Angioli, R, Liotta, LA, Pecorelli, SL, Petricoin, EF & 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, vol. 117, no. 4, pp. 494-502. https://doi.org/10.1038/bjc.2017.195
Sereni, Maria Isabella ; Baldelli, Elisa ; Gambara, Guido ; Ravaggi, Antonella ; Hodge, K. Alex ; Alberts, David S ; Guillen-Rodriguez, Jose M. ; Dong, Ting ; Memo, Maurizio ; Odicino, Franco ; Angioli, Roberto ; Liotta, Lance A. ; Pecorelli, Sergio L. ; Petricoin, Emanuel F. ; Pierobon, Mariaelena. / Kinase-driven metabolic signalling as a predictor of response to carboplatin-paclitaxel adjuvant treatment in advanced ovarian cancers. In: British Journal of Cancer. 2017 ; Vol. 117, No. 4. pp. 494-502.
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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.",
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T1 - Kinase-driven metabolic signalling as a predictor of response to carboplatin-paclitaxel adjuvant treatment in advanced ovarian cancers

AU - Sereni, Maria Isabella

AU - Baldelli, Elisa

AU - Gambara, Guido

AU - Ravaggi, Antonella

AU - Hodge, K. Alex

AU - Alberts, David S

AU - Guillen-Rodriguez, Jose M.

AU - Dong, Ting

AU - Memo, Maurizio

AU - Odicino, Franco

AU - Angioli, Roberto

AU - Liotta, Lance A.

AU - Pecorelli, Sergio L.

AU - Petricoin, Emanuel F.

AU - Pierobon, Mariaelena

PY - 2017/8/8

Y1 - 2017/8/8

N2 - 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.

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KW - reverse phase protein microarray

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