Kinase-driven Metabolic Signalling As a Predictor of Response to Carboplatin-paclitaxel Adjuvant Treatment in Advanced Ovarian Cancers

Overview

Journal Br J Cancer

Specialty Oncology

Date 2017 Jul 1

PMID 28664915

Citations 7

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

Upregulation of p300 in paclitaxel-resistant TNBC: implications for cell proliferation via the PCK1/AMPK axis.

Zhao P, Cui J, Wang X Pharmacogenomics J. 2024; 24(2):5.

PMID: 38378770 DOI: 10.1038/s41397-024-00324-3.

PD-L1 quantification across tumor types using the reverse phase protein microarray: implications for precision medicine.

Baldelli E, Alex Hodge K, Bellezza G, Shah N, Gambara G, Sidoni A J Immunother Cancer. 2021; 9(10).

PMID: 34620701 PMC: 8499669. DOI: 10.1136/jitc-2020-002179.

Laser Capture Proteomics: spatial tissue molecular profiling from the bench to personalized medicine.

Liotta L, Pappalardo P, Carpino A, Haymond A, Howard M, Espina V Expert Rev Proteomics. 2021; 18(10):845-861.

PMID: 34607525 PMC: 10720974. DOI: 10.1080/14789450.2021.1984886.

Wild-Type KRAS Allele Effects on Druggable Targets in KRAS Mutant Lung Adenocarcinomas.

Baldelli E, El Gazzah E, Moran J, Hodge K, Manojlovic Z, Bassiouni R Genes (Basel). 2021; 12(9).

PMID: 34573384 PMC: 8467269. DOI: 10.3390/genes12091402.

The impact of ultraviolet- and infrared-based laser microdissection technology on phosphoprotein detection in the laser microdissection-reverse phase protein array workflow.

Hunt A, Pierobon M, Baldelli E, Oliver J, Mitchell D, Gist G Clin Proteomics. 2020; 17:9.

PMID: 32165870 PMC: 7061469. DOI: 10.1186/s12014-020-09272-z.

References

Valente G, Morani F, Nicotra G, Fusco N, Peracchio C, Titone R . Expression and clinical significance of the autophagy proteins BECLIN 1 and LC3 in ovarian cancer. Biomed Res Int. 2014; 2014:462658. PMC: 4127242. DOI: 10.1155/2014/462658. View

Wang J, Pan X, Ding L, Liu D, Lei D, Jin T . Aberrant expression of Beclin-1 and LC3 correlates with poor prognosis of human hypopharyngeal squamous cell carcinoma. PLoS One. 2013; 8(7):e69038. PMC: 3723780. DOI: 10.1371/journal.pone.0069038. View

Pin E, Federici G, Petricoin 3rd E . Preparation and use of reverse protein microarrays. Curr Protoc Protein Sci. 2014; 75:27.7.1-27.7.29. DOI: 10.1002/0471140864.ps2707s75. View

Eijkelenboom A, Burgering B . FOXOs: signalling integrators for homeostasis maintenance. Nat Rev Mol Cell Biol. 2013; 14(2):83-97. DOI: 10.1038/nrm3507. View

Vivanco I, Sawyers C . The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002; 2(7):489-501. DOI: 10.1038/nrc839. View

Shackelford D, Shaw R . The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 2009; 9(8):563-75. PMC: 2756045. DOI: 10.1038/nrc2676. View

Thiery J . Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002; 2(6):442-54. DOI: 10.1038/nrc822. View

Dilokthornsakul P, Chaiyakunapruk N, Termrungruanglert W, Pratoomsoot C, Saokaew S, Sruamsiri R . The effects of metformin on ovarian cancer: a systematic review. Int J Gynecol Cancer. 2013; 23(9):1544-51. DOI: 10.1097/IGC.0b013e3182a80a21. View

Therasse P, Arbuck S, Eisenhauer E, Wanders J, Kaplan R, Rubinstein L . New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000; 92(3):205-16. DOI: 10.1093/jnci/92.3.205. View

10.

Mueller C, deCarvalho A, Mikkelsen T, Lehman N, Calvert V, Espina V . Glioblastoma cell enrichment is critical for analysis of phosphorylated drug targets and proteomic-genomic correlations. Cancer Res. 2013; 74(3):818-28. DOI: 10.1158/0008-5472.CAN-13-2172. View

11.

Sereni M, Baldelli E, Gambara G, Deng J, Zanotti L, Bandiera E . Functional characterization of epithelial ovarian cancer histotypes by drug target based protein signaling activation mapping: implications for personalized cancer therapy. Proteomics. 2014; 15(2-3):365-73. DOI: 10.1002/pmic.201400214. View

12.

Rattan R, Giri S, Hartmann L, Shridhar V . Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner. J Cell Mol Med. 2009; 15(1):166-78. PMC: 3822503. DOI: 10.1111/j.1582-4934.2009.00954.x. View

13.

Liu P, Cheng H, Roberts T, Zhao J . Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009; 8(8):627-44. PMC: 3142564. DOI: 10.1038/nrd2926. View

14.

Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong Z . AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 2013; 17(1):113-24. PMC: 3545102. DOI: 10.1016/j.cmet.2012.12.001. View

15.

Zeppernick F, Meinhold-Heerlein I . The new FIGO staging system for ovarian, fallopian tube, and primary peritoneal cancer. Arch Gynecol Obstet. 2014; 290(5):839-42. DOI: 10.1007/s00404-014-3364-8. View

16.

Li C, Liu V, Chiu P, Chan D, Ngan H . Over-expressions of AMPK subunits in ovarian carcinomas with significant clinical implications. BMC Cancer. 2012; 12:357. PMC: 3518102. DOI: 10.1186/1471-2407-12-357. View

17.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

18.

Signore M, Reeder K . Antibody validation by Western blotting. Methods Mol Biol. 2011; 823:139-55. DOI: 10.1007/978-1-60327-216-2_10. View

19.

Nelson M, Radmacher M, Simon R, Aickin M, Yang J, Panda L . Chromosome abnormalities in malignant melanoma: clinical significance of nonrandom chromosome abnormalities in 206 cases. Cancer Genet Cytogenet. 2000; 122(2):101-9. DOI: 10.1016/s0165-4608(00)00281-8. View

20.

Pierobon M, Ramos C, Wong S, Alex Hodge K, Aldrich J, Byron S . Enrichment of PI3K-AKT-mTOR Pathway Activation in Hepatic Metastases from Breast Cancer. Clin Cancer Res. 2017; 23(16):4919-4928. PMC: 5564311. DOI: 10.1158/1078-0432.CCR-16-2656. View