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FGFR4 has been reported to have antifibrotic effects in the liver. We aimed to determine the involvement of FGFR4 during IPF. Our data suggest that FGFR4 exerts profibrotic properties by enhancing TGF-β signaling in vitro. However, the inhibition of FGFR4 is not sufficient to prevent the development of pulmonary fibrosis in vivo. To our knowledge, this is the first study to assess the profibrotic action of FGFR4 during pulmonary fibrosis.

01 Apr 2024·Cellular Oncology

The leukemia inhibitory factor regulates fibroblast growth factor receptor 4 transcription in gastric cancer

Article

Author: Cari, Luigi ; Sepe, Valentina ; Bordoni, Martina ; Urbani, Ginevra ; Massa, Carmen ; Monti, Maria Chiara ; Rapacciuolo, Pasquale ; Bellini, Rachele ; Fiorucci, Stefano ; Zampella, Angela ; Donini, Annibale ; Lupia, Antonio ; Distrutti, Eleonora ; Marchianò, Silvia ; Di Giorgio, Cristina ; Ullah, Khan Rana Sami ; Rosselli, Rosalinda ; Catalanotti, Bruno ; Morretta, Elva ; Moraca, Federica ; Natalizi, Nicola ; De Gregorio, Rosa ; Graziosi, Luigina ; Biagioli, Michele

AbstractPurposeThe gastric adenocarcinoma (GC) represents the third cause of cancer-related mortality worldwide, and available therapeutic options remain sub-optimal. The Fibroblast growth factor receptors (FGFRs) are oncogenic transmembrane tyrosine kinase receptors. FGFR inhibitors have been approved for the treatment of various cancers and a STAT3-dependent regulation of FGFR4 has been documented in the H.pylori infected intestinal GC. Therefore, the modulation of FGFR4 might be useful for the treatment of GC.MethodsTo investigate wich factors could modulate FGFR4 signalling in GC, we employed RNA-seq analysis on GC patients biopsies, human patients derived organoids (PDOs) and cancer cell lines.ResultsWe report that FGFR4 expression/function is regulated by the leukemia inhibitory factor (LIF) an IL-6 related oncogenic cytokine, in JAK1/STAT3 dependent manner. The transcriptomic analysis revealed a direct correlation between the expression of LIFR and FGFR4 in the tissue of an exploratory cohort of 31 GC and confirmed these findings by two external validation cohorts of GC. A LIFR inhibitor (LIR-201) abrogates STAT3 phosphorylation induced by LIF as well as recruitment of pSTAT3 to the promoter of FGFR4. Furthermore, inhibition of FGFR4 by roblitinib or siRNA abrogates STAT3 phosphorylation and oncogentic effects of LIF in GC cells, indicating that FGFR4 is a downstream target of LIF/LIFR complex. Treating cells with LIR-201 abrogates oncogenic potential of FGF19, the physiological ligand of FGFR4.ConclusionsTogether these data unreveal a previously unregnized regulatory mechanism of FGFR4 by LIF/LIFR and demonstrate that LIF and FGF19 converge on the regulation of oncogenic STAT3 in GC cells.Graphical abstract

22 Apr 2023·Journal of experimental & clinical cancer research : CR

FGFR4 and EZH2 inhibitors synergistically induce hepatocellular carcinoma apoptosis via repressing YAP signaling.

Article

Author: Li, Fu ; Li, Jingsheng ; Zhang, Linhao ; Yang, Yiqi ; Zhang, Bihui ; Zhang, Jinting ; Zhang, Yibo ; Su, Zijian ; Xie, Junye ; Liu, Rongzhan ; Cao, Jieqiong ; Zhang, Peiguang ; Hong, An ; Chen, Xiaojia

BACKGROUNDHepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide, but current treatment options remain limited and cause serious life-threatening side effects. Aberrant FGFR4 signaling has been validated as an oncogenic driver of HCC, and EZH2, the catalytic subunit of the PRC2 complex, is a potential factor that contributes to acquired drug resistance in many tumors, including HCC. However, the functional relationship between these two carcinogenic factors, especially their significance for HCC treatment, remains unclear. In this study, we systematically evaluated the feasibility of a combination therapy targeting FGFR4 and EZH2 for HCC.METHODSRNA sequencing data of patients with Liver hepatocellular carcinoma (LIHC) from The Cancer Genome Atlas (TCGA) were analyzed to determine FGFR4 and EZH2 expression and their interaction with prognosis. Moreover, the HCC cell lines, zebrafish/mouse HCC xenografts and zebrafish HCC primary tumors were treated with FGFR4 inhibitor (Roblitinib) and/or EZH2 inhibitor (CPI-169) and then subjected to cell proliferation, viability, apoptosis, and tumor growth analyses to evaluate the feasibility of combination therapy for HCC both in vitro and in vivo. Furthermore, RNA-Seq was performed in combination with ChIP-Seq data analysis to investigate the critical mechanism underlying the combination treatment with Roblitinib and CPI-169.RESULTSEZH2 accumulated through the non-canonical NF-kB signaling in response to FGFR4 inhibitor treatment, and the elevated EZH2 levels led to the antagonism of HCC against Roblitinib (FGFR4 inhibitor). Notably, knockdown of EZH2 sensitized HCC cells to Roblitinib, while the combination treatment of Roblitinib and CPI-169 (EZH2 inhibitor) synergistically induced the HCC cell apoptosis in vitro and suppressed the zebrafish/mouse HCC xenografts and zebrafish HCC primary tumors development in vivo. Moreover, Roblitinib and CPI-169 synergistically inhibited HCC development via repressing YAP signaling.CONCLUSIONSCollectively, our study highlighted the potential of the therapeutic combination of FGFR4 and EZH2 inhibitors, which would provide new references for the further development of clinical treatment strategies for HCC.

100 Deals associated with Roblitinib

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Phase 1	CN	Novartis Pharma AG	29 Dec 2014
Malignant Solid Neoplasm	Discovery	SG	Beijing Novartis Pharma Co. Ltd.	29 Dec 2014
Malignant Solid Neoplasm	Discovery	IT	Novartis Pharma AG	29 Dec 2014
Malignant Solid Neoplasm	Discovery	SG	Novartis Pharma AG	29 Dec 2014
Malignant Solid Neoplasm	Discovery	KR	Beijing Novartis Pharma Co. Ltd.	29 Dec 2014
Malignant Solid Neoplasm	Discovery	KR	Novartis Pharma AG	29 Dec 2014
Malignant Solid Neoplasm	Discovery	ES	Novartis Pharma AG	29 Dec 2014
Malignant Solid Neoplasm	Discovery	DE	Novartis Pharma AG	29 Dec 2014
Malignant Solid Neoplasm	Discovery	JP	Beijing Novartis Pharma Co. Ltd.	29 Dec 2014
Malignant Solid Neoplasm	Discovery	DE	Beijing Novartis Pharma Co. Ltd.	29 Dec 2014

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02325739 (AACR2017)	Phase 2	Hepatocellular Carcinoma	172	NVP-FGF401	lfnaujokqr(elyiwuaptf) = qfdjyihtyo bpifhyigif (rypdeprbgb )	-	01 Jul 2017
NCT02325739 (AACR2017)	Phase 1/2	FGFR4 positive Solid Tumors	67	FGF401	(dojmnzqrsb) = tultzrhnip cqelyfxtbl (kmjfzxqdsl ) View more	Positive	01 Jul 2017