Co-activation of the invasion and survival contributes to transformation induced by exon 14 splicing of MET receptor in lung cancer - Archive ouverte HAL Accéder directement au contenu
Poster De Conférence Année : 2019

Co-activation of the invasion and survival contributes to transformation induced by exon 14 splicing of MET receptor in lung cancer

Résumé

Background : Although the majority of RTK mutations impact the kinase domain, those affecting the MET receptor in lung cancer cause exon 14 splicing (MET ex14) resulting in loss of a regulatory domain. Patients with these mutations are eligible for treatment with MET inhibitors, however it is necessary to understand MET activation in this context. The juxtamembrane domain contains at least three negative regulatory sites. Among them, phosphorylable residues S985 and Y1003 respectively allow inhibition of kinase activity and degradation of MET in response to its ligand HGF. Moreover, the ESVD1002 motif is a caspase cleavage site involved in pro-apoptotic activity in the absence of ligand. Objectives : Determine the contribution of each regulatory sites in transforming capacities of MET ex14 cells. Methods : We have developed epithelial cell lines expressing MET versions, WT, exon 14 deleted or mutated on each or all of these regulatory sites. In parallel, we established by CRISPR-Cas9 pulmonary epithelial lines expressing MET ex14, MET Y1003F mutant and MET V1001A + Y1003F double mutant. Results : In response to HGF, mutation on Y1003 induces a stronger and longer signaling pathway activation associated with a greater invasive potential. On the other hand, the mutation of the caspase cleavage site favors cell survival. Interestingly, the MET ex14 receptor exhibits both an increase in signaling pathway activation and invasive processes and a greater survival. These data suggest a combined action of these gains of function to induce a complete cell transformation. Our goal is now to evaluate the contribution of these regulatory mechanisms to tumor growth, which both depends on the invasive and survival capacities of tumor cells. Xenografts are performing in immunodeficient mice expressing human HGF thus allowing the activation of MET receptor. Conclusion : Our results show the role of MET ex14 in a co-activation of invasion and survival which supports the use of tyrosine kinase inhibitor targeting MET for these patients but also calls into question the use of pro-apoptotic chemotherapies.
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hal-04559723 , version 1 (25-04-2024)

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  • HAL Id : hal-04559723 , version 1

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Marie Fernandes, Sonia Paget, Zoulika Kherrouche, Anne Chotteau-Lelièvre, Luca Grumolato, et al.. Co-activation of the invasion and survival contributes to transformation induced by exon 14 splicing of MET receptor in lung cancer. 3rd International Symposium Research on Healthy Ageing, Dec 2019, Lille, France. ⟨hal-04559723⟩
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