FGFR2 fusion proteins drive oncogenic transformation of mouse liver organoids towards cholangiocarcinoma was written by Cristinziano, Giulia;Porru, Manuela;Lamberti, Dante;Buglioni, Simonetta;Rollo, Francesca;Amoreo, Carla Azzurra;Manni, Isabella;Giannarelli, Diana;Cristofoletti, Cristina;Russo, Giandomenico;Borad, Mitesh J.;Grazi, Gian Luca;Diodoro, Maria Grazia;Giordano, Silvia;Sacconi, Andrea;Forcato, Mattia;Anastasi, Sergio;Leonetti, Carlo;Segatto, Oreste. And the article was included in Journal of Hepatology in 2021.Application of 872511-34-7 This article mentions the following:
About 15% of intrahepatic cholangiocarcinomas (iCCAs) express fibroblast growth factor receptor 2 (FGFR2) fusion proteins (FFs), usually alongside mutational inactivation of TP53, CDKN2A or BAP1. In FFs, FGFR2 residues 1-768 fuse to sequences encoded by a diverse array of partner genes (>60) causing oncogenic FF activation. While FGFR-specific tyrosine kinase inhibitors (F-TKI) provide clin. benefit in FF+ iCCA, responses are partial and/or limited by resistance mechanisms, such as the V565F substitution in the FGFR2 gatekeeper residue. Improving on FF targeting in iCCA therefore remains a critical unmet need. Herein, we aimed to generate a murine model of FF-driven iCCA and use this to uncover actionable FF-associated dependencies.Four iCCA FFs carrying different fusion sequences were expressed in Tp53-/- mouse liver organoids. Tumorigenic properties of genetically modified liver organoids were assessed by transplantation into immuno-deficient mice. Cellular models derived from neoplastic lesions were exploited for pre-clin. studies.Transplantation of FF-expressing liver organoids yielded tumors diagnosed as CCA based on histol., phenotypic and transcriptomic analyses. The penetrance of this tumorigenic phenotype was influenced by FF identity. Tumor organoids and 2D cell lines derived from CCA lesions were addicted to FF signaling via Ras-Erk, regardless of FF identity or V565F mutation. Dual blockade of FF and the Ras-Erk pathway by concomitant pharmacol. inhibition of FFs and Mek1/2 provided greater therapeutic efficacy than single agent F-TKI in vitro and in vivo.FF-driven iCCA pathogenesis was successfully modeled on a Tp53-/- murine background, revealing biol. heterogeneity among structurally different FFs. Double blockade of FF-ERK signaling deserves consideration for precision-based approaches against human FF+ iCCA.Intrahepatic cholangiocarcinoma (iCCA) is a rare cancer that is difficult to treat. A subtype of iCCA is caused by genomic alterations that generate oncogenic drivers known as FGFR2 fusions. Patients with FGFR2 fusions respond to FGFR inhibitors, but clin. responses are often of modest duration. We used animal and cellular models to show that FGFR2 fusions require the activity of a downstream effector named Mek1/2. We found that dual blockade of FGFR2 fusions and Mek1/2 was more effective than isolated inhibition of FGFR2 fusions, pointing to the potential clin. utility of dual FGFR2-MEK1/2 blockade in patients with iCCA. In the experiment, the researchers used many compounds, for example, 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-(6-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-1-methylurea (cas: 872511-34-7Application of 872511-34-7).
3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-(6-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-1-methylurea (cas: 872511-34-7) belongs to piperazine derivatives. Simple N-substituted piperazines have been found in many drug molecules. Outside the body, piperazine has a remarkable power to dissolve uric acid and producing a soluble urate, but in clinical experience it has not proved equally successful. Application of 872511-34-7
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