Fibroblast growth factor receptor fusions in cancer: opportunities and challenges

Chen, Lingfeng; Zhang, Yanmei; Yin, Lilin; Cai, Binhao; Huang, Ping; Li, Xiaokun; Liang, Guang

doi:10.1186/s13046-021-02156-6

Cited by 31 publications

(24 citation statements)

References 101 publications

(136 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Human iCCA is characterized by insidious onset, clinical aggressiveness, and a lack of effective treatments [ 1 – 5 ]. Therefore, the molecular pathogenesis of iCCA should be deciphered to identify novel targets and establish more effective therapies.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The Hippo pathway effector TAZ induces intrahepatic cholangiocarcinoma in mice and is ubiquitously activated in the human disease

Cigliano

Zhang

Ribback

et al. 2022

J Exp Clin Cancer Res

View full text Add to dashboard Cite

Background Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive primary liver tumor with increasing incidence worldwide, dismal prognosis, and few therapeutic options. Mounting evidence underlines the role of the Hippo pathway in this disease; however, the molecular mechanisms whereby the Hippo cascade contributes to cholangiocarcinogenesis remain poorly defined. Methods We established novel iCCA mouse models via hydrodynamic transfection of an activated form of transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo pathway downstream effector, either alone or combined with the myristoylated AKT (myr-AKT) protooncogene, in the mouse liver. Hematoxylin and eosin staining, immunohistochemistry, electron microscopy, and quantitative real-time RT-PCR were applied to characterize the models. In addition, in vitro cell line studies were conducted to address the growth-promoting roles of TAZ and its paralog YAP. Results Overexpression of TAZ in the mouse liver triggered iCCA development with very low incidence and long latency. In contrast, co-expression of TAZ and myr-AKT dramatically increased tumor frequency and accelerated cancer formation in mice, with 100% iCCA incidence and high tumor burden by 10 weeks post hydrodynamic injection. AKT/TAZ tumors faithfully recapitulated many of the histomolecular features of human iCCA. At the molecular level, the development of the cholangiocellular lesions depended on the binding of TAZ to TEAD transcription factors. In addition, inhibition of the Notch pathway did not hamper carcinogenesis but suppressed the cholangiocellular phenotype of AKT/TAZ tumors. Also, knockdown of YAP, the TAZ paralog, delayed cholangiocarcinogenesis in AKT/TAZ mice without affecting the tumor phenotype. Furthermore, human preinvasive and invasive iCCAs and mixed hepatocellular carcinoma/iCCA displayed widespread TAZ activation and downregulation of the mechanisms protecting TAZ from proteolysis. Conclusions Overall, the present data underscore the crucial role of TAZ in cholangiocarcinogenesis

show abstract

Section: Discussionmentioning

confidence: 99%

“…iCCA is a deadly disease with few treatment options [ 1 – 5 ]. Therefore, to significantly improve the prognosis of iCCA patients, a better understanding of the molecular pathogenesis of this tumor type is highly required.…”

Section: Introductionmentioning

confidence: 99%

The Hippo pathway effector TAZ induces intrahepatic cholangiocarcinoma in mice and is ubiquitously activated in the human disease

Cigliano

Zhang

Ribback

et al. 2022

J Exp Clin Cancer Res

View full text Add to dashboard Cite

show abstract

“…18 FGFRs belong to the highly conserved single-transmembrane tyrosine receptor family, which consist of extracellular ligand binding domains and cytoplasmic conservative tyrosine kinase. 19 The FGFR family includes receptors FGFR1−4 that are individually encoded but highly homologous to vascular endothelial growth factor receptors, platelet-derived growth factor receptors and other tyrosine kinase receptors. 20 , 21 An abnormal FGFR signaling pathway has become an important cause of many tumors.…”

Section: Discussionmentioning

confidence: 99%

“…FGF, FGFR and heparan sulfate proteoglycan form a 2:2:2 ternary complex, which causes dimerization of receptors and transphosphorylation of kinases, which then activates the PI3K-AKT, RAS-MEK-ERK, PLC-γ, and JAK-STAT3 signaling pathways. 19 , 22 Most fusion partners contain dimers that dimerize non-ligand receptors, leading to proliferation of cancer cells, metastasis, and angiogenesis. 23 , 24 …”

Section: Discussionmentioning

confidence: 99%

FGFR2-ERC1: A Subtype of FGFR2 Oncogenic Fusion Variant in Lung Adenocarcinoma and the Response to Anlotinib

Hong¹,

Weng²,

Zhou³

et al. 2022

OTT

View full text Add to dashboard Cite

Background Fibroblast growth factor receptor (FGFR) fusions in non-small cell lung cancer (NSCLC) are small genomic events. At present, there is no standard treatment strategy for patients with NSCLC carrying an FGFR fusion. Case Presentation We report the case of a 45-year-old female patient who was diagnosed with lung adenocarcinoma and underwent right upper lobectomy and postoperative adjuvant chemotherapy. After 13 months, the patient’s lung lesions progressed. Next-generation sequencing of venous blood and lung tissues confirmed an FGFR2-ERC1 fusion, and she received chemotherapy and immunotherapy. Two months later, the patient’s lung lesions progressed again. Based on the target effect of anlotinib on FGFR, the patient was subsequently treated with anlotinib, and the progression-free survival interval exceeded 8.0 months. Conclusion These findings showed that patients with lung adenocarcinoma carrying an FGFR2-ERC1 fusion gene may benefit from anlotinib. This case provided evidence to support the use of anlotinib in the treatment of NSCLC patients with FGFR fusion gene subtypes.

show abstract

“…Both these gene mutations are used to identify new therapeutic targets and further our understanding of existing ones [8]. Erdafitinib and pemigatinib, two FGFR selective inhibitors targeting FGFR fusions, have been approved by the U.S. Food and Drug Administration (FDA) to treat patients with urothelial cancer and cholangiocarcinoma, respectively [9,10], and there is hope that these inhibitors could be used for HNSCC also.…”

Section: Introductionmentioning

confidence: 99%

Understanding the Pattern of Oropharyngeal Cancers from North-East Romanian Patients

et al. 2021

View full text Add to dashboard Cite

Background: Human papilloma virus (HPV) is acknowledged as a risk factor for oropharyngeal squamous cellular cancers (OPSCC), of which the dominant types are tonsillar (TSCC) and base of tongue cancer (BOTSCC). Objective: To assess the role of HPV in selected OPSCC cases, from Romanian patients by sensitive and complementary molecular assays. Material and Methods: Fifty-four formalin fixed paraffin embedded (FFPE) OPSCC samples were analyzed for HPV DNA by a PCR-based bead-based multiplex-assay. Thirty-four samples were tested for HPV RNA and for overexpression of p16INK4a by immunohistochemistry. Twenty samples were evaluated by Competitive Allele-Specific Taqman PCR (CAST-PCR) for fibroblast growth factor receptor 3 protein (FGFR3) status. Results: A total of 33.3% (18/54) OPSCC samples were positive for HPV DNA. HPV16 was the most frequent type (30%, 16/54); followed by HPV18 (3.7%, 2/54); and 1 sample (1.8%) was positive for both HPV16 and 18. HPV18 E6*I was detected in a HPV18 DNA-positive oropharynx tumor. Four samples positive for HPV16 were also positive for p16INK4a. All the tested samples were negative for FGFR3. Conclusions: The increased HPV16 prevalence is in line with similar studies and is a new confirmation that HPV16 is the most prevalent type in our country; supporting the potential benefit of prophylactic vaccines. Overall, there is no concordance between DNA and any of the two other analytes that are considered being markers of HPV-driven cancers. There is a need to explore novel screening strategies that could be broadly used in the clinical routine to initiate preventive measures.

show abstract

Fibroblast growth factor receptor fusions in cancer: opportunities and challenges

Cited by 31 publications

References 101 publications

The Hippo pathway effector TAZ induces intrahepatic cholangiocarcinoma in mice and is ubiquitously activated in the human disease

The Hippo pathway effector TAZ induces intrahepatic cholangiocarcinoma in mice and is ubiquitously activated in the human disease

FGFR2-ERC1: A Subtype of FGFR2 Oncogenic Fusion Variant in Lung Adenocarcinoma and the Response to Anlotinib

Understanding the Pattern of Oropharyngeal Cancers from North-East Romanian Patients

Contact Info

Product

Resources

About