azd-6244 and Carcinogenesis

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.

Topics: Animals; Antineoplastic Agents; Benzimidazoles; Biomarkers, Tumor; Carcinogenesis; Cell Line, Tumor; Cystadenocarcinoma, Serous; Female; Humans; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Mice; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Ovarian Neoplasms; Prognosis; Proto-Oncogene Proteins; Ribosomal Protein S6 Kinases, 90-kDa; Xenograft Model Antitumor Assays