title: MAP3K8/TPL-2/COT is a potential predictive marker for MEK inhibitor treatment in high-grade serous ovarian carcinomas.
abstract: Ovarian cancer is a silent disease with a poor prognosis that urgently requires new therapeutic strategies. In low-grade ovarian tumours, mutations in the MAP3K BRAF gene constitutively activate the downstream kinase MEK. Here we demonstrate that an additional MAP3K, MAP3K8 (TPL-2/COT), accumulates in high-grade serous ovarian carcinomas (HGSCs) and is a potential prognostic marker for these tumours. By combining analyses on HGSC patient cohorts, ovarian cancer cells and patient-derived xenografts, we demonstrate that MAP3K8 controls cancer cell proliferation and migration by regulating key players in G1/S transition and adhesion dynamics. In addition, we show that the MEK pathway is the main pathway involved in mediating MAP3K8 function, and that MAP3K8 exhibits a reliable predictive value for the effectiveness of MEK inhibitor treatment. Our data highlight key roles for MAP3K8 in HGSC and indicate that MEK inhibitors could be a useful treatment strategy, in combination with conventional chemotherapy, for this disease.
authors.affiliation: Stress and Cancer Laboratory, Institut Curie, 26, rue d'Ulm, Paris 75248, France.|Inserm, Genetics and Biology of Cancers, U830, Paris F-75248, France.
authors.forename: Tina
authors.initials: T
authors.lastname: Gruosso
authors.affiliation: Stress and Cancer Laboratory, Institut Curie, 26, rue d'Ulm, Paris 75248, France.|Inserm, Genetics and Biology of Cancers, U830, Paris F-75248, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Garnier
authors.affiliation: Stress and Cancer Laboratory, Institut Curie, 26, rue d'Ulm, Paris 75248, France.|Inserm, Genetics and Biology of Cancers, U830, Paris F-75248, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Abelanet
authors.affiliation: Stress and Cancer Laboratory, Institut Curie, 26, rue d'Ulm, Paris 75248, France.|Inserm, Genetics and Biology of Cancers, U830, Paris F-75248, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Kieffer
authors.affiliation: Stress and Cancer Laboratory, Institut Curie, 26, rue d'Ulm, Paris 75248, France.|Inserm, Genetics and Biology of Cancers, U830, Paris F-75248, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Lemesre
authors.affiliation: Inserm, Genetics and Biology of Cancers, U830, Paris F-75248, France.|Genomics and Biology of the Hereditary Breast Cancers, Institut Curie, 26, rue d'Ulm, Paris 75248, France.
authors.forename: Dorine
authors.initials: D
authors.lastname: Bellanger
authors.affiliation: Department of Pharmacogenomics, Institut Curie, 26, rue d'Ulm, Paris 75248, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bieche
authors.affiliation: Translational Research Department, Laboratory of Precinical Investigation, Institut Curie, 26, rue d'Ulm, Paris 75248, France.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Marangoni
authors.affiliation: Department of Pathology, Institut Curie, 26, rue d'Ulm, Paris 75248, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Sastre-Garau
authors.affiliation: Stress and Cancer Laboratory, Institut Curie, 26, rue d'Ulm, Paris 75248, France.|Inserm, Genetics and Biology of Cancers, U830, Paris F-75248, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Mieulet
authors.affiliation: Stress and Cancer Laboratory, Institut Curie, 26, rue d'Ulm, Paris 75248, France.|Inserm, Genetics and Biology of Cancers, U830, Paris F-75248, France.
authors.forename: Fatima
authors.initials: F
authors.lastname: Mechta-Grigoriou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D018284:Cystadenocarcinoma, Serous / Q000175:diagnosis / Q000188:drug therapy / Q000201:enzymology*; D005260:Female; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000201:enzymology*; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C517975:AZD 6244; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D014408:Biomarkers, Tumor; D011518:Proto-Oncogene Proteins; C581313:binimetinib; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases