Dual targeting of G9a and DNMT1 for the treatment of experimental cholangiocarcinoma
Leticia Colyn, Marina Bárcena-Varela, Gloria Álvarez-Sola, M Ujue Latasa, Iker Uriarte, Eva Santamaría, Jose M Herranz, Alvaro Santos-Laso, Maria Arechederra, Mikel Ruiz de Gauna, Patricia Aspichueta, Matteo Canale, Andrea Casadei-Gardini, Maria Francesconi, Simone Carotti, Sergio Morini, Leonard J Nelson, Maria J Iraburu, Chaobo Chen, Bruno Sangro, Jose Jg Marin, Maria L Martinez-Chantar, Jesus M Banales, Robert Arnes, Meritxell Huch, John Patino, Altaf A Dar, Mehdi Nosrati, Julen Oyarzábal, Felipe Prósper, Jesus Urman, Francisco Javier Cubero, Christian Trautwein, Carmen Berasain, Maite G Fernandez-Barrena, Matias A Avila
Background & 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 new therapeutic opportunities. However, modifications such as DNA and histone methylation often co-exist and cooperate in carcinogenesis. We tested the therapeutic efficacy and mechanism of action of a new class of dual G9a histone-methyltransferase and DNA-methyltransferase 1 (DNMT1) inhibitors.
Approach & 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, patients-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. Co-treatment with independent pharmacological inhibitors G9a and DNMT1 synergistically inhibited CCA cell growth. CM272 markedly reduced CCA cells 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 towards a differentiated and quiescent status.
Conclusions: Dual targeting of G9a and DNMT1 with epigenetic small molecule inhibitors such as CM272 is a potential novel strategy to treat CCA and/or to enhance the efficacy of other systemic therapies.
CITA DEL ARTÍCULO Hepatology. 2020 Nov 22. doi: 10.1002/hep.31642. Online ahead of print.