The Application Progress of Patient-Derived Tumor Xenograft Models After Cholangiocarcinoma Surgeries

Wu, Jun; Sheng, Jiyao; Qin, Hanjiao; Cui, Mengying; Yang, Yongsheng; Zhang, Xuewen

doi:10.3389/fonc.2021.628636

Cited by 5 publications

(3 citation statements)

References 90 publications

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“…Tasurgratinib showed antitumor activity in allografts of NIH/3T3 expressing the FGFR2fusion gene. We also used CCA PDX models to reinforce the preclinical evidence of tasurgratinib because these models are supposed to reflect the genetic, histopathological, and phenotypic characteristics of patients with CCA (46). Western blot analyses were performed to elucidate the molecular mechanism of action of tasurgratinib against preclinical CCA models with the FGFR2-fusion gene.…”

Section: Discussionmentioning

confidence: 99%

Antitumor Activity of Tasurgratinib as an Orally Available FGFR1-3 Inhibitor in Cholangiocarcinoma Models With FGFR2-fusion

KAWANO,

KAWADA,

FUKUSHIMA

et al. 2024

Anticancer Res

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Background/Aim: Cholangiocarcinoma (CCA) is an aggressive tumor with limited treatment options especially in 2nd line or later treatments. Targeting fibroblast growth factor receptor (FGFR) 2 has recently emerged as a promising treatment option for patients with CCA harboring FGFR2-fusion. This study investigated the antitumor activities of tasurgratinib as an orally available FGFR1-3 inhibitor, in preclinical FGFR2-driven CCA models. Materials and Methods: Antitumor activities of tasurgratinib were examined in vitro and in vivo using NIH/3T3 cells expressing FGFR2-fusion as FGFR2-driven CCA models, and in vivo using a CCA patient-derived xenograft model. The molecular mechanism of action of tasurgratinib was elucidated through co-crystal structure analysis with FGFR1, manual complex model analysis with FGFR2, and binding kinetics analysis with FGFR2. Furthermore, the cell-based inhibitory activities against acquired resistant FGFR2 mutations in patients with CCA treated with FGFR inhibitors were evaluated. Results: Tasurgratinib showed antitumor activity in preclinical FGFR2-driven CCA models by inhibiting the FGFR signaling pathway in vitro and in vivo. Furthermore, cell-based target engagement assays indicated that tasurgratinib had potent inhibitory activities against FGFR2 mutations, such as N549H/K, which are the major acquired mutations in CCA. We also confirmed that tasurgratinib exhibited fast association and slow dissociation kinetics with FGFR2, binding to the ATP-binding site and the neighboring region, and adopting an Asp-Phe-Gly (DFG)-"in" conformation. Conclusion: These data demonstrate the therapeutic potential of tasurgratinib in FGFR2-driven CCA and provide molecular mechanistic insights into its unique inhibitory profile against secondary FGFR2 resistance mutations in patients with CCA treated with FGFR inhibitors.Cholangiocarcinoma (CCA) is the second-most common primary hepatic malignancy worldwide. It accounts for approximately 30% of all primary liver cancers and is associated with a high mortality rate owing to few symptoms in its early stages and frequent diagnosis at an advanced stage (1, 2). Incidence rates have increased over the past decade, with an annual incidence of 2000-3000 cases in the United States (3). However, the incidence of CCA is much higher in Asian countries, including Japan and China (4). CCA is often diagnosed after the disease significantly progresses when it is unresectable. In addition to gemcitabine plus cisplatin as the standard of care, durvalumab plus gemcitabine and cisplatin was recently approved and recommended as first-line treatment for patients with advanced stage; however, the prognosis remains poor, and more effective treatment strategies are warranted (5, 6).The Fibroblast growth factor receptor (FGFR) family of tyrosine kinases receptors consists of four genes that encode transmembrane receptors that bind to FGF on the extracellular domain. Upon binding to a ligand, a signaling cascade induces several cellular functions, including the proliferation, s...

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Section: Discussionmentioning

confidence: 99%

Antitumor Activity of Tasurgratinib as an Orally Available FGFR1-3 Inhibitor in Cholangiocarcinoma Models With FGFR2-fusion

KAWANO,

KAWADA,

FUKUSHIMA

et al. 2024

Anticancer Res

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“…It's a remarkable fact that PDX models cannot suffer from too many passages, because in that case the stroma is replaced by the components of the mouse. 47 , 48 Cells are dissociated from tumor tissues or PDX to prepare a cell suspension, which is then transplanted. This procedure avoids the above problems and increases the tumorigenesis rate.…”

Section: Sources Of Xenograft Tumorsmentioning

confidence: 99%

Towards an optimal model for gastric cancer peritoneal metastasis: current challenges and future directions

Li¹,

Wang²,

Wang³

et al. 2023

eBioMedicine

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“…The tumors are more likely to form and the sizes are easier to be monitored in subcutaneous transplantation models. Orthotopic transplantation models provide a better original tumor microenvironment, however, the operations may be more complex ( 111 ).…”

Section: Patient-derived Drug Resistance Modelsmentioning

confidence: 99%

Advances in Renal Cell Carcinoma Drug Resistance Models

Xiang

Zheng²,

Zhong³

et al. 2022

Front. Oncol.

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Renal cell carcinoma (RCC) is the most common form of kidney cancer. Systemic therapy is the preferred method to eliminate residual cancer cells after surgery and prolong the survival of patients with inoperable RCC. A variety of molecular targeted and immunological therapies have been developed to improve the survival rate and prognosis of RCC patients based on their chemotherapy-resistant properties. However, owing to tumor heterogeneity and drug resistance, targeted and immunological therapies lack complete and durable anti-tumor responses; therefore, understanding the mechanisms of systemic therapy resistance and improving clinical curative effects in the treatment of RCC remain challenging. In vitro models with traditional RCC cell lines or primary cell culture, as well as in vivo models with cell or patient-derived xenografts, are used to explore the drug resistance mechanisms of RCC and screen new targeted therapeutic drugs. Here, we review the established methods and applications of in vivo and in vitro RCC drug resistance models, with the aim of improving our understanding of its resistance mechanisms, increasing the efficacy of combination medications, and providing a theoretical foundation for the development and application of new drugs, drug screening, and treatment guidelines for RCC patients.

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The Application Progress of Patient-Derived Tumor Xenograft Models After Cholangiocarcinoma Surgeries

Cited by 5 publications

References 90 publications

Antitumor Activity of Tasurgratinib as an Orally Available FGFR1-3 Inhibitor in Cholangiocarcinoma Models With FGFR2-fusion

Antitumor Activity of Tasurgratinib as an Orally Available FGFR1-3 Inhibitor in Cholangiocarcinoma Models With FGFR2-fusion

Towards an optimal model for gastric cancer peritoneal metastasis: current challenges and future directions

Advances in Renal Cell Carcinoma Drug Resistance Models

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