New Opportunity for a IHC CDx assay predicting MEK inhibitors efficacy in high-grade ovarian cancers
inhibitors efficacy in high-grade ovarian cancers for licencing
- high-grade EOC represent a high unmet medical need
- 50% high-grade EOCs have a MEK-activated pathway
- The MEK kinase, COT/MAP3K8, could be a valuable biomarker for predicting mek inhibitors efficacy in high-grade EOC
We showed that MAP3K8 controls cancer cell proliferation and migration by regulating key players in G1/S transition and adhesion dynamics. Importantly, there is a significant correlation between MAP3K8 protein level and MEK activation in human high-grade EOCs, supporting that MAP3K8 can be used as readout for MEK activation. Moreover, MAP3K8 exhibits a reliable predictive value for the efficiency of MEK inhibitors in high-grade EOCs. Indeed, using Patient-derived xenograft mouse models of high-grade EOCs, we established that MEK inhibitors significantly reduce tumour growth in tumours in which MAP3K8 accumulates (50% cases). Thus, if anti-MEK therapies have been included in clinical trials for low-grade EOC, due to the prevalence of KRAS/BRAF mutations that invariably result in constitutive MEK activation, our results demonstrate that high-grade EOC patients with COT/MAP3K8 accumulation might also greatly benefit of anti-MEK treatments combined to conventional chemotherapies.
We are seeking a co-development or licensing partner to validate this biomarker/CDx through a clinical study
A wide proteomic analysis enabled us to uncover constitutive activation of MEK/ERK pathway in 50% cases of high-grade EOC. While the majority of low-grade EOC harbour KRAS/BRAF mutations that result invariably in constitutive MEK activation (BRAF being a MEK Kinase), less than 1% of high-grade EOC exhibit KRAS/BRAF mutations. Still, half high-grade EOC exhibit constitutive MEK/ERK activation, due to accumulation of COT/MAP3K8, the other MEK kinase besides BRAF.
CDx through IHC assay
MAP3K8/TPL-2/COT is a potential predictive marker for MEK inhibitor treatment in high-grade serous ovarian carcinomas.
Gruosso T, Garnier C, Abelanet S, Kieffer Y, Lemesre V, Bellanger D, Bieche I, Marangoni E, Sastre-Garau X, Mieulet V, Mechta-Grigoriou F