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

Persistent Link:
http://hdl.handle.net/10150/625488
Title:
Kinase-driven metabolic signalling as a predictor of response to carboplatin–paclitaxel adjuvant treatment in advanced ovarian cancers
Author:
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
Affiliation:
Univ Arizona, Ctr Canc
Issue Date:
2017-06-29
Publisher:
NATURE PUBLISHING GROUP
Citation:
Kinase-driven metabolic signalling as a predictor of response to carboplatin–paclitaxel adjuvant treatment in advanced ovarian cancers 2017, 117 (4):494 British Journal of Cancer
Journal:
British Journal of Cancer
Rights:
Copyright © 2017, Rights Managed by Nature Publishing Group
Collection Information:
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
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 AMPK alpha T172, AMPK alpha 1 S485, AMPK beta 1 S108, AKT S473 and T308, mTOR S2448, p70S6 S371, 4EBP1 S65, GSK-3 alpha/beta 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.
Note:
12 month embargo; published online: 29 June 2017 / Creative Commons Attribution-NonCommercial-Share-Alike 3.0
ISSN:
0007-0920; 1532-1827
DOI:
10.1038/bjc.2017.195
Keywords:
ovarian cancer; kinase signalling; metabolism; reverse phase protein microarray; chemo-sensitivity
Version:
Final published version
Sponsors:
College of Science, George Mason University, the Istituto Superiore di Sanita (Programma Italia-USA Oncoproteomica) [527/B4/4]; University of Brescia, Italy
Additional Links:
http://www.nature.com/doifinder/10.1038/bjc.2017.195

Full metadata record

DC FieldValue Language
dc.contributor.authorSereni, Maria Isabellaen
dc.contributor.authorBaldelli, Elisaen
dc.contributor.authorGambara, Guidoen
dc.contributor.authorRavaggi, Antonellaen
dc.contributor.authorHodge, K Alexen
dc.contributor.authorAlberts, David Sen
dc.contributor.authorGuillen-Rodriguez, Jose Men
dc.contributor.authorDong, Tingen
dc.contributor.authorMemo, Maurizioen
dc.contributor.authorOdicino, Francoen
dc.contributor.authorAngioli, Robertoen
dc.contributor.authorLiotta, Lance Aen
dc.contributor.authorPecorelli, Sergio Len
dc.contributor.authorPetricoin, Emanuel Fen
dc.contributor.authorPierobon, Mariaelenaen
dc.date.accessioned2017-09-13T23:29:39Z-
dc.date.available2017-09-13T23:29:39Z-
dc.date.issued2017-06-29-
dc.identifier.citationKinase-driven metabolic signalling as a predictor of response to carboplatin–paclitaxel adjuvant treatment in advanced ovarian cancers 2017, 117 (4):494 British Journal of Canceren
dc.identifier.issn0007-0920-
dc.identifier.issn1532-1827-
dc.identifier.doi10.1038/bjc.2017.195-
dc.identifier.urihttp://hdl.handle.net/10150/625488-
dc.description.abstractBackground: 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 AMPK alpha T172, AMPK alpha 1 S485, AMPK beta 1 S108, AKT S473 and T308, mTOR S2448, p70S6 S371, 4EBP1 S65, GSK-3 alpha/beta 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.en
dc.description.sponsorshipCollege of Science, George Mason University, the Istituto Superiore di Sanita (Programma Italia-USA Oncoproteomica) [527/B4/4]; University of Brescia, Italyen
dc.language.isoenen
dc.publisherNATURE PUBLISHING GROUPen
dc.relation.urlhttp://www.nature.com/doifinder/10.1038/bjc.2017.195en
dc.rightsCopyright © 2017, Rights Managed by Nature Publishing Groupen
dc.subjectovarian canceren
dc.subjectkinase signallingen
dc.subjectmetabolismen
dc.subjectreverse phase protein microarrayen
dc.subjectchemo-sensitivityen
dc.titleKinase-driven metabolic signalling as a predictor of response to carboplatin–paclitaxel adjuvant treatment in advanced ovarian cancersen
dc.typeArticleen
dc.contributor.departmentUniv Arizona, Ctr Cancen
dc.identifier.journalBritish Journal of Canceren
dc.description.note12 month embargo; published online: 29 June 2017 / Creative Commons Attribution-NonCommercial-Share-Alike 3.0en
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
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