Arnes-Benito, R. (Robert)

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    Identification of PRMT5 as a therapeutic target in cholangiocarcinoma
    (BMJ, 2024) Elurbide, J. (Jasmin); Colyn, L. (Leticia); Latasa, M.U. (María Ujué); Uriarte, I. (Iker); Mariani, S. (Stefano); Lopez-Pascual, A. (Amaya); Valbuena, E. (Emiliana); Castelló-Uribe, B. (Borja); Arnes-Benito, R. (Robert); Adán-Villaescusa, E. (Elena); Martínez-Pérez, L. (L.); Azkargorta, M. (Mikel); Elortza, F. (Felix); Wu, H. (Hanghang); Krawczyk, M. (Marcin); Schneider, K.M. (Kai Markus); Sangro, B. (Bruno); Aldrighetti, L. (Luca); Ratti, F. (Francesca); Casadei-Gardini, A. (Andrea); Marin, J.J.G (Jose J.G.); Amat, I. (Irene); Urman, J.M. (Jesús M.); Arechederra, M. (María); Martinez-Chantar, M.L. (María Luz); Trautwein, C. (Christian); Huch, M. (Meritxell); Cubero, F.J. (Francisco Javier); Berasain, C. (Carmen); Fernández-Barrena, M.G. (Maite G.); Avila, M.A. (Matías Antonio)
    Background: Cholangiocarcinoma (CCA) is a very difficult-to-treat cancer. Chemotherapies are little effective and response to immune checkpoint inhibitors is limited. Therefore, new therapeutic strategies need to be identified. Objective: We characterised the enzyme protein arginine-methyltransferase 5 (PRMT5) as a novel therapeutic target in CCA. Design: We evaluated the expression of PRMT5, its functional partner MEP50 and methylthioadenosine phosphorylase (MTAP)-an enzyme that modulates the sensitivity of PRMT5 to pharmacological inhibitors-in human CCA tissues. PRMT5-targeting drugs, currently tested in clinical trials for other malignancies, were assessed in human CCA cell lines and organoids, as well as in two immunocompetent CCA mouse models. Transcriptomic, proteomic and functional analyses were performed to explore the underlying antitumoural mechanisms. Results: PRMT5 and MEP50 proteins were correlatively overexpressed in most CCA tissues. MTAP was absent in 25% of intrahepatic CCA. PRMT5-targeting drugs markedly inhibited CCA cell proliferation, synergising with cisplatin and gemcitabine and hindered the growth of cholangiocarcinoma organoids. PRMT5 inhibition blunted the expression of oncogenic genes involved in chromatin remodelling and DNA repair, consistently inducing the formation of RNA loops and promoting DNA damage. Treatment with PRMT5-targeting drugs significantly restrained the growth of experimental CCA without adverse effects and concomitantly induced the recruitment of CD4 and CD8 T cells to shrinking tumourous lesions. Conclusion: PRMT5 and MEP50 are frequently upregulated in human CCA, and PRMT5-targeting drugs have significant antitumoural efficacy in clinically relevant CCA models. Our findings support the evaluation of PRMT5 inhibitors in clinical trials, including their combination with cytotoxic and immune therapies.
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    Dual Targeting of G9a and DNA Methyltransferase-1 for the Treatment of Experimental Cholangiocarcinoma
    (2021) Colyn, L. (Leticia); Bárcena-Varela, M. (Marina); Álvarez-Sola, G. (Gloria); Latasa, M.U. (María Ujué); Uriarte, I. (Iker); Santamaría, E. (Eva); Herranz, J.M. (José M.); Santos-Laso, A. (Alvaro); Arechederra, M. (María); Ruiz-de-Gauna, M. (Mikel); Aspichueta, P. (Patricia); Canale, M. (Matteo); Casadei-Gardini, A. (Andrea); Francesconi y Suffo, José Maria de los Reyes; Carotti, S. (Simone); Morini, S. (Sergio); Nelson, L.J. (Leonard J.); Iraburu-Elizalde, M.J. (María José); Chen, C. (Chaobo); Sangro, B. (Bruno); Marin, J.J.G (Jose J.G.); Martinez-Chantar, M.L. (María Luz); Banales, J.M. (Jesús M.); Arnes-Benito, R. (Robert); Huch, M. (Meritxell); Oyarzabal, J. (Julen); Prosper-Cardoso, F. (Felipe); Urman, J.M. (Jesús M.); García-Fernandez-Barrena, M. (Maite); Cubero, F.J. (Francisco Javier); Trautwein, C. (Christian); Berasain-Lasarte, M. (María del Carmen); Avila, M.A. (Matías Antonio)
    Background and aims: Cholangiocarcinoma (CCA) is a devastating disease often detected at advanced stages when surgery cannot be performed. Conventional and targeted systemic therapies perform poorly, and therefore effective drugs are urgently needed. Different epigenetic modifications occur in CCA and contribute to malignancy. Targeting epigenetic mechanisms may thus open therapeutic opportunities. However, modifications such as DNA and histone methylation often coexist and cooperate in carcinogenesis. We tested the therapeutic efficacy and mechanism of action of a class of dual G9a histone-methyltransferase and DNA-methyltransferase 1 (DNMT1) inhibitors. Approach and results: Expression of G9a, DNMT1, and their molecular adaptor, ubiquitin-like with PHD and RING finger domains-1 (UHRF1), was determined in human CCA. We evaluated the effect of individual and combined pharmacological inhibition of G9a and DNMT1 on CCA cell growth. Our lead G9a/DNMT1 inhibitor, CM272, was tested in human CCA cells, patient-derived tumoroids and xenograft, and a mouse model of cholangiocarcinogenesis with hepatocellular deletion of c-Jun-N-terminal-kinase (Jnk)-1/2 and diethyl-nitrosamine (DEN) plus CCl4 treatment (JnkΔhepa + DEN + CCl4 mice). We found an increased and correlative expression of G9a, DNMT1, and UHRF1 in CCAs. Cotreatment with independent pharmacological inhibitors G9a and DNMT1 synergistically inhibited CCA cell growth. CM272 markedly reduced CCA cell proliferation and synergized with Cisplatin and the ERBB-targeted inhibitor, Lapatinib. CM272 inhibited CCA tumoroids and xenograft growth and significantly antagonized CCA progression in JnkΔhepa + DEN + CCl4 mice without apparent toxicity. Mechanistically, CM272 reprogrammed the tumoral metabolic transcriptome and phenotype toward a differentiated and quiescent status. Conclusions: Dual targeting of G9a and DNMT1 with epigenetic small molecule inhibitors such as CM272 is a potential strategy to treat CCA and/or enhance the efficacy of other systemic therapies.