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

Author

Listed:
  • Tina Gruosso

    (Stress and Cancer Laboratory, Institut Curie
    Inserm, Genetics and Biology of Cancers, U830)

  • Camille Garnier

    (Stress and Cancer Laboratory, Institut Curie
    Inserm, Genetics and Biology of Cancers, U830)

  • Sophie Abelanet

    (Stress and Cancer Laboratory, Institut Curie
    Inserm, Genetics and Biology of Cancers, U830)

  • Yann Kieffer

    (Stress and Cancer Laboratory, Institut Curie
    Inserm, Genetics and Biology of Cancers, U830)

  • Vincent Lemesre

    (Stress and Cancer Laboratory, Institut Curie
    Inserm, Genetics and Biology of Cancers, U830)

  • Dorine Bellanger

    (Inserm, Genetics and Biology of Cancers, U830
    Genomics and Biology of the Hereditary Breast Cancers, Institut Curie)

  • Ivan Bieche

    (Institut Curie)

  • Elisabetta Marangoni

    (Laboratory of Precinical Investigation, Institut Curie)

  • Xavier Sastre-Garau

    (Institut Curie)

  • Virginie Mieulet

    (Stress and Cancer Laboratory, Institut Curie
    Inserm, Genetics and Biology of Cancers, U830)

  • Fatima Mechta-Grigoriou

    (Stress and Cancer Laboratory, Institut Curie
    Inserm, Genetics and Biology of Cancers, U830)

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.

Suggested Citation

  • Tina Gruosso & Camille Garnier & Sophie Abelanet & Yann Kieffer & Vincent Lemesre & Dorine Bellanger & Ivan Bieche & Elisabetta Marangoni & Xavier Sastre-Garau & Virginie Mieulet & Fatima Mechta-Grigo, 2015. "MAP3K8/TPL-2/COT is a potential predictive marker for MEK inhibitor treatment in high-grade serous ovarian carcinomas," Nature Communications, Nature, vol. 6(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9583
    DOI: 10.1038/ncomms9583
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    Cited by:

    1. Monika Licaj & Rana Mhaidly & Yann Kieffer & Hugo Croizer & Claire Bonneau & Arnaud Meng & Lounes Djerroudi & Kevin Mujangi-Ebeka & Hocine R. Hocine & Brigitte Bourachot & Ilaria Magagna & Renaud Lecl, 2024. "Residual ANTXR1+ myofibroblasts after chemotherapy inhibit anti-tumor immunity via YAP1 signaling pathway," Nature Communications, Nature, vol. 15(1), pages 1-27, December.

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