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.
Highlights
Ovarian cancer is a silent disease with a poor prognosis that urgently requires new therapeutic strategies
MAP3K8 accumulation is of poor prognosis in high-grade serous ovarian carcinomas (HGSCs) patients
This MAP3K8 prognostic value only relates to protein and not messenger RNA levels, most probably because MAP3K8 mRNA and protein levels do not correlate in HGSC (Supplementary Fig. 1C)
Summary
Ovarian cancer is a silent disease with a poor prognosis that urgently requires new therapeutic strategies. 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. Patients are initially quite sensitive to conventional platinum–taxane chemotherapy, most women relapse and die of the disease This alarming observation highlights the urgent need to decipher ovarian tumours at a molecular level to develop more effective therapeutic strategies. Following treatment with BRAF inhibitors, some patients exhibit a chronic MEK activation and develop resistance through constitutive expression of the serine threonine kinase MAP3K8/TPL-2/COT, the other MAP3K upstream of MEK14,17. As there are no fully validated targetable molecular markers currently available for this pathology, our data indicate that MAP3K8/ TPL-2/COT could be such a biomarker and define MEK inhibitors as a new promising therapeutic option for HGSC patients, in combination with conventional therapy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
