Figure 6: MAP3K8 exhibits pro-tumorigenic properties in HGSC and is a predictive marker for treatment with MEK inhibitor.

Among epithelial ovarian cancers, the serous histological subtype is the most abundant and is subdivided into two subgroups according to grade (low versus high grade). Seventy percent cases of low-grade ovarian carcinomas exhibited KRAS or BRAF mutations and subsequent MEK activation, which led to the use of MEK inhibitors as a new line of treatment in recent clinical trials with some relevant efficiency. In contrast, KRAS or BRAF mutations remain extremely rare in HGSC (less than 1%). Yet, we demonstrate here that the MEK pathway is constitutively activated in half cases of HGSC. MAP3K8 (also referred as TPL-2 or COT) accumulation in HGSC mediates this constitutive MEK/ERK pathway activation, MAP3K8 being the other MEK kinase, besides RAF. MAP3K8 contributes to tumour growth via p90RSK-dependent regulation of cyclin D1 and FAK, key regulators of the G1/S transition and adhesion dynamics, respectively. Therefore, our study demonstrates for the first time that the use of MEK inhibitors should not be restricted to low-grade ovarian carcinomas, as they are currently in clinical trials, but could be extended to patients suffering from HGSC characterized by MAP3K8 accumulation.