Carmen Berasain1,2,3, Maite G Fernandez-Barrena1,2,3, Matias A Avila1,2,3, Leticia Colyn1, Marina Bárcena-Varela1, Gloria Álvarez-Sola1,2, M Ujue Latasa1, Iker Uriarte1,2, Eva Santamaría1,2, Jose M Herranz1,2, Alvaro Santos-Laso4, Maria Arechederra1, Mikel Ruiz de Gauna5, Patricia Aspichueta5, Matteo Canale6, Andrea Casadei-Gardini7, Maria Francesconi8, Simone Carotti8,9, Sergio Morini8, Leonard J Nelson10, Maria J Iraburu11, Chaobo Chen12, Bruno Sangro2,13,3, Jose J G Marin2,14, Maria L Martinez-Chantar2,15, Jesus M Banales2,4, Robert Arnes-Benito16, Meritxell Huch16, John M Patino17, Altaf A Dar17, Mehdi Nosrati17, Julen Oyarzábal18, Felipe Prósper3,19, Jesus Urman3,20, Francisco Javier Cubero12, Christian Trautwein21. 1. Hepatology Program, CIMA, University of Navarra, Pamplona, Spain. 2. CIBERehd, Instituto de Salud Carlos III, Madrid, Spain. 3. Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain. 4. Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, Ikerbasque, Donostia-San Sebastian, Spain. 5. Biocruces Health Research Institute, Department of Physiology, University of the Basque Country, Leioa, Spain. 6. Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. 7. School of Medicine, Vita-Salute San Raffaele University and Unit of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. 8. Unit of Microscopic and Ultrastructural Anatomy, University Campus Bio-Medico, Rome, Italy. 9. Predictive Molecular Diagnostic Division, Pathology Department, Campus Bio-Medico University Hospital, Rome, Italy. 10. School of Engineering, Institute of Engineering, The University of Edimburgh, Edimburgh, United Kingdom. 11. Department of Biochemistry and Genetics, University of Navarra, Pamplona, Spain. 12. Department of Immunology, Ophtalmology and ENT, School of Medicine, Complutense University, Madrid, Spain. 13. Hepatology Unit, Navarra University Clinic, Pamplona, Spain. 14. Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, Salamanca, Spain. 15. Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CICbioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain. 16. Max Plank Institute of Molecular Cell Biology and Genetics, Dresden, Germany. 17. California Pacific Medical Center Research Institute, San Francisco, CA. 18. Molecular Therapies Program, CIMA, University of Navarra, Pamplona, Spain. 19. Oncohematology Program, CIMA, University of Navarra, Pamplona, Spain. 20. Department of Digestive Diseases, Complejo Hospitalario de Navarra, Pamplona, Spain. 21. Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
Abstract
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.
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.
Authors: Leticia Colyn; Gloria Alvarez-Sola; M Ujue Latasa; Carmen Berasain; Maite G Fernandez-Barrena; Matias A Avila; Iker Uriarte; Jose M Herranz; Maria Arechederra; George Vlachogiannis; Colin Rae; Antonio Pineda-Lucena; Andrea Casadei-Gardini; Federica Pedica; Luca Aldrighetti; Angeles López-López; Angeles López-Gonzálvez; Coral Barbas; Sergio Ciordia; Sebastiaan M Van Liempd; Juan M Falcón-Pérez; Jesus Urman; Bruno Sangro; Silve Vicent; Maria J Iraburu; Felipe Prosper; Leonard J Nelson; Jesus M Banales; Maria Luz Martinez-Chantar; Jose J G Marin; Chiara Braconi; Christian Trautwein; Fernando J Corrales; F Javier Cubero Journal: J Exp Clin Cancer Res Date: 2022-05-26
Authors: Chaobo Chen; Hanghang Wu; Hui Ye; Agustín Tortajada; Sandra Rodríguez-Perales; Raúl Torres-Ruiz; August Vidal; Maria Isabel Peligros; Johanna Reissing; Tony Bruns; Mohamed Ramadan Mohamed; Kang Zheng; Amaia Lujambio; Maria J Iraburu; Leticia Colyn; Maria Ujue Latasa; María Arechederra; Maite G Fernández-Barrena; Carmen Berasain; Javier Vaquero; Rafael Bañares; Leonard J Nelson; Christian Trautwein; Roger J Davis; Eduardo Martinez-Naves; Yulia A Nevzorova; Alberto Villanueva; Matias A Avila; Francisco Javier Cubero Journal: Cancers (Basel) Date: 2021-12-24 Impact factor: 6.639
Authors: Mandy Schott; Melanie Kappelmann-Fenzl; Stefan Fischer; Maite G Fernandez-Barrena; Antonio Pineda-Lucena; Matías A Ávila; Silke Kuphal; Anja-Katrin Bosserhoff Journal: Int J Mol Med Date: 2022-03-16 Impact factor: 4.101