The PI3K/AKT/mTOR pathway plays a major role in melanoma pathogenesis and is also involved in resistance to targeted therapies (TT). The mTORC2 complex plays an important role in this pathway and therefore contributes to the development of BRAF-mutated (BRAFm) melanomas and their resistance to treatments. The goal of our project is to study this complex in melanoma in order to target it specifically. For this purpose, we are focusing more particularly on one principal protein of this complex: SIN1 (also called MAPKAP1). We are analysing SIN1 expression, by quantitative RT-PCR and IHC and its interaction with other proteins, by Proximity Ligation Assay (PLA), in situ in melanoma biopsies of the French national MELBASE cohort. We will correlate these results with clinico-biological data from MELBASE to determine if there is a diagnostic or prognostic value of these analyses. In a second step, we are mapping the minimal domain of SIN1/NRAS interaction by Peptide Array to develop cell-permeable peptides to inhibit NRAS/mTORC2 interaction. Furthermore, we are evaluating whether SIN1 has also functions independent of the mTORC2 complex in melanoma, by searching for other partners of SIN1 by PLA in melanoma lines. Finally, we are studying the role of SIN1/mTORC2 on the PD-L1 expression (programmed death-ligand 1) induced by interferon (IFN), and therefore the immune checkpoint inhibitors response in melanoma. Our preliminary results show that mTORC2 interacts with NRAS in BRAFm melanoma and that inhibiting the NRAS/mTORC2 interaction reduces the proliferation of melanoma cell lines and in particular those resistant to TT. This leads us to develop inhibitors to specifically target resistant melanomas. The results of this project will provide us a better understanding of the SIN1/mTORC2 signalling pathway in the development of BRAFm melanoma and its response to TT. Given the lack of a specific mTORC2 inhibitor at this time, SIN1 could be an ideal therapeutic target to aim for mTORC2.

The PI3K/AKT/mTOR pathway plays a major role in melanoma pathogenesis and is also involved in resistance to targeted therapies (TT). The mTORC2 complex plays an important role in this pathway and therefore contributes to the development of BRAF-mutated (BRAFm) melanomas and their resistance to treatments. The goal of our project is to study this complex in melanoma in order to target it specifically. For this purpose, we are focusing more particularly on one principal protein of this complex: SIN1 (also called MAPKAP1). We are analysing SIN1 expression, by quantitative RT-PCR and IHC and its interaction with other proteins, by Proximity Ligation Assay (PLA), in situ in melanoma biopsies of the French national MELBASE cohort. We will correlate these results with clinico-biological data from MELBASE to determine if there is a diagnostic or prognostic value of these analyses. In a second step, we are mapping the minimal domain of SIN1/RAS interaction by Peptide Array to develop cell-permeable peptides to inhibit RAS/mTORC2 interaction. Furthermore, we are evaluating whether SIN1 has also functions independent of the mTORC2 complex in melanoma, by searching for other partners of SIN1 by PLA in melanoma lines. Finally, we are studying the role of SIN1/mTORC2 on the PD-L1 expression (programmed death-ligand 1) induced by interferon (IFN), and therefore the immune checkpoint inhibitors response in melanoma. Our preliminary results show that mTORC2 interacts with NRAS in BRAFm melanoma and that inhibiting the NRAS/mTORC2 interaction reduces the proliferation of melanoma cell lines and in particular those resistant to TT. This leads us to develop inhibitors to specifically target resistant melanomas. The results of this project will provide us a better understanding of the SIN1/mTORC2 signalling pathway in the development of BRAFm melanoma and its response to TT. Given the lack of a specific mTORC2 inhibitor at this time, SIN1 could be an ideal therapeutic target to aim for mTORC2.

ESDR471 - mTORC2: therapeutic target in resistant BRAF-mutated melanoma

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.