MAP3K8/TPL-2/COT is a potential predictive marker for MEK inhibitor treatment in high-grade serous ovarian carcinomas

  • Nat Commun. 2015 Oct 12:6:8583. doi: 10.1038/ncomms9583.
Tina Gruosso  1  2 ,  Camille Garnier  1  2 ,  Sophie Abelanet  1  2 ,  Yann Kieffer  1  2 ,  Vincent Lemesre  1  2 ,  Dorine Bellanger  2  3 ,  Ivan Bieche  4 ,  Elisabetta Marangoni  5 ,  Xavier Sastre-Garau  6 ,  Virginie Mieulet  1  2 ,  Fatima Mechta-Grigoriou  1  2
Affiliations
  • 1. Stress and Cancer Laboratory, Institut Curie, 26, rue d'Ulm, Paris 75248, France.
  • 2. Inserm, Genetics and Biology of Cancers, U830, Paris F-75248, France.
  • 3. Genomics and Biology of the Hereditary Breast Cancers, Institut Curie, 26, rue d'Ulm, Paris 75248, France.
  • 4. Department of Pharmacogenomics, Institut Curie, 26, rue d'Ulm, Paris 75248, France.
  • 5. Translational Research Department, Laboratory of Precinical Investigation, Institut Curie, 26, rue d'Ulm, Paris 75248, France.
  • 6. Department of Pathology, Institut Curie, 26, rue d'Ulm, Paris 75248, France.
PMID: 26456302 DOI: 10.1038/ncomms9583
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.