P13.15.B STRONG EVIDENCES TO TARGET YAP1/TAZ-TEAD IN MENINGIOMA: PRECLINICAL STUDY.

Abstract BACKGROUND the therapeutic management for recurrent meningioma remains an unmet need. Accumulating evidences over few years highlight the interest of targeting HIPPO pathway in cancers and more specifically the final effector complex: YAP1/TAZ-TEAD transcription factors. Biallelic inactivation of NF2 is the initiating event in the around 60 % of sporadic meningiomas. NF2/Merlin loss is associated also to an inactivation of the HIPPO repressor pathway inducing a YAP1/TAZ-TEAD transcriptional activity. MATERIAL AND METHODS using 3 different meningioma cell lines and a large series of fresh meningiomas, the role of the Hippo pathway was studied on 91 meningiomas, well characterized at clinical, histological and molecular level. The genomic profile, target transcripts of the complex YAP1/TAZ-TEADs, cell viability, and cell proliferation were analyzed after i) siRNA transfection targeting YAP1, TAZ, YAP1+TAZ and TEADs and ii) after treatment with six YAP1/TAZ-TEADs inhibitors (IV1 to IV6) or combined with MAPKinase (Trametinib) or Pi3K-AKT-mTOR (Everolimus) inhibitors. RESULTS inactivation of the YAP1/TAZ-TEAD by siRNA or by IV3 and IV6 who bind to the TEAD Ω-loop pocket inhibits cell proliferation and weakly affects cell viability. The transcriptional inhibition of CTGF and CYR61 targeted genes by these siRNA or by IV3 or IV6 demonstrate the engagement of YAP1/TAZ-TEAD complex in this effect. These effects were observed in NF2 deficient (def) and in NF2 wild type (wt) tumors. The higher expression of TEAD target genes CTGF and CYR61 in NF2def tumors vs NF2wt ones, supported the higher activity of YAP1/TAZ-TEAD transcriptional activity in NF2def tumors. However more that NF2 mutation, the NF2 protein level seems crucial since an inverse correlation between NF2 protein level and CTGF mRNA was observed. Combination of YAP1/TAZ-TEADs inhibitors with MAPKinase or Pi3K-AKT-mTOR inhibitors induced a significant stronger decrease in cell proliferation than each drug alone. An additive effect was observed between IV3 and IV6 and Everolimus or Trametinib. CONCLUSION Conclusion: our study highlights the potential therapeutic interest of targeting YAP1/TAZ-TEAD activity to control tumor growth of meningiomas, and to set up a clinical trial not only in NF2def tumors but in all meningiomas and suggests the potential interest of a co-targeting therapy with MAPKinase or Pi3K-AKT-mTOR inhibitors. This work was supported by Inventiva.