Pazopanib, a Novel Multitargeted Kinase Inhibitor, Shows Potent<i>In Vitro</i>Antitumor Activity in Gastric Cancer Cell Lines with<i>FGFR2</i>Amplification

Kim, Seung Tae; Jang, Hyung Suk; Lee, Su Jin; Lee, Jeeyun; Choi, Yoon La; Cho, Jeonghee; Park, Se Hoon; Park, Young Suk; Lim, Ho Yeong; Yashiro, Masakazu; Kang, Won Ki; Park, Joon Oh

doi:10.1158/1535-7163.mct-14-0255

Cited by 36 publications

(20 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…By investigating the efficacy of two different TKIs, a cytostatic effect was noted exclusively with pazopanib. Kim et al (41) reported potent anti-tumoral activity in gastric cancer cell lines harboring FGFR2 amplification. Although FGFR2 mutations appear in only 9% of HNSCC cases, they have no significant impact on Table V.…”

Section: Discussionmentioning

confidence: 99%

Targeting VEGFR and FGFR in head and neck squamous cell carcinoma in vitro

et al. 2017

View full text Add to dashboard Cite

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease characterized by a tumor microenvironment (TME) that overexpresses vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR), which can lead to neovascularization, tumor growth and metastasis. Therapeutic strategies inhibiting these signaling pathways might lead to innovative HNSCC treatments. Five HNSCC cell lines were characterized based on VEGFR1-3 and FGFR1-4 expression by sqRT-PCR and treated with three different tyrosine kinase inhibitors (TKIs) (nintedanib, dovitinib and pazopanib), all of which are effective against VEGFR and FGFR family members. Crystal violet assays were performed to analyze the effect of the treatments on cell growth (viability). Additionally, VEGFR1-3 and FGFR1-4 expression data were retrieved from The Cancer Genome Atlas (TCGA), and statistical analyses were performed to investigate the receptor expression level in the different cell lines and the efficacy of the single-agent treatments. A correlation analysis was performed to quantify the degree of relationship between receptor expression and drug efficacy. With the exception of VEGFR2, the targeted receptors were expressed at different levels in all of the cell lines. The cell lines exhibited concentration-dependent responses with cell line-specific differences toward two of the three TKIs (nintedanib and dovitinib). Notably, all of the cell lines were resistant to pazopanib. TKIs have potential as therapeutic agents for HNSCC. Cell line-specific differences were observed in our in vitro experiments. The observed pazopanib resistance could be explained by receptor expression. Further investigation is required to determine TKI efficacy in HNSCC.

show abstract

Section: Discussionmentioning

confidence: 99%

Targeting VEGFR and FGFR in head and neck squamous cell carcinoma in vitro

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Targeted drugs are currently being developed for patients with GC that exhibit FGFR2 gene amplification [9,17,18,19,20,31]. A phase II FGFR2-targeted trial has been completed (although not yet published) [32] and another study is ongoing [33].…”

Section: Discussionmentioning

confidence: 99%

“…FGFR2 amplification has been reported to occur in 2-9% of GC and is associated with shorter survival [10,11,12,13,14,15,16]. Recent studies of FGFR inhibitors in GC cell lines have given promising results [9,17,18,19,20], suggesting that FGFR2 is a potential molecular target for the treatment of a subset of GC.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Fibroblast Growth Factor Receptor 2 Expression, Heterogeneity and Clinical Significance in Gastric Cancer

Han¹,

Kim²,

Lee³

et al. 2015

Pathobiology

View full text Add to dashboard Cite

Background: We aimed to evaluate the protein and mRNA expression of fibroblast growth factor receptor 2 (FGFR2) by immunohistochemistry (IHC) and mRNA in situ hybridization (ISH), respectively, and to assess the heterogeneity of FGFR2 expression in gastric cancer (GC). Methods: A tissue microarray containing 362 surgically resected GC tissues and 135 matched metastatic lymph nodes was evaluated using FGFR2b IHC and FGFR2 ISH. FGFR2 fluorescence ISH was also performed in 188 cases. Results: All FGFR2-amplified cases (5 of 188) showed FGFR2b protein and FGFR2 mRNA overexpression (p < 0.001), and FGFR2 amplification was not identified in FGFR2b IHC- and FGFR2 mRNA ISH-negative cases. Kaplan-Meier survival analysis revealed that FGFR2b protein and FGFR2 mRNA overexpression was significantly associated with a poor overall survival (p < 0.001 and p = 0.012, respectively), and multivariate analyses showed that FGFR2 mRNA overexpression was an independent biomarker of a poor overall survival. Intratumoral heterogeneity of FGFR2b protein and FGFR2 mRNA overexpression was observed in 5 of 9 (55.5%) and 18 of 21 (85.7%) cases, respectively. Discordant FGFR2b and FGFR2 expression results between primary and matched metastatic lymph nodes were observed in 5 of 9 (55.5%) and 4 of 14 (28.6%) cases, respectively. Conclusions: Intratumoral heterogeneity and discordant FGFR2b expression in primary tumors and metastatic lymph nodes are common in GC.

show abstract

“…The incidence of amplification is estimated to be around 5-10% among gastric cancers (Matsumoto et al, 2012;Su et al, 2014). Hence, there is significant interest in FGFR2 as a therapeutic target for FGFR2-amplified gastric cancers, and preclinical and clinical evaluation of FGFR inhibitors are actively ongoing (Chang et al, 2015;Gozgit et al, 2012;Kim et al, 2014;Xie et al, 2013). In other types of gastrointestinal cancers including colorectal cancers, hepatocellular carcinoma, and pancreatobiliary cancers, FGFR2 amplification is not frequently demonstrated (Dieci et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

FGFR2 amplification is predictive of sensitivity to regorafenib in gastric and colorectal cancers in vitro

et al. 2018

View full text Add to dashboard Cite

Although regorafenib has demonstrated survival benefits in patients with metastatic colorectal and gastrointestinal stromal tumors, no proven biomarker has been identified for predicting sensitivity to regorafenib. Here, we investigated preclinical activity of regorafenib in gastric and colorectal cancer cells to identify genetic alterations associated with sensitivity to regorafenib. Mutation profiles and copy number assays of regorafenib target molecules indicated that amplification of fibroblast growth factor receptor 2 (FGFR2) was the only genetic alteration associated with in vitro sensitivity to regorafenib. Regorafenib effectively inhibited phosphorylation of FGFR2 and its downstream signaling molecules in a dose‐dependent manner and selectively in FGFR2‐amplified cells. Regorafenib induced G1 arrest (SNU‐16, KATO‐III) and apoptosis (NCI‐H716); however, no significant changes were seen in cell lines without FGFR2 amplification. In SNU‐16 mice xenografts, regorafenib significantly inhibited tumor growth, proliferation, and FGFR signaling compared to treatment with control vehicle. Regorafenib effectively abrogates activated FGFR2 signaling in FGFR2‐amplified gastric and colorectal cancer and, therefore, might be considered for integration into treatment in patients with FGFR2‐amplified gastric and colorectal cancers.

show abstract

Pazopanib, a Novel Multitargeted Kinase Inhibitor, Shows PotentIn VitroAntitumor Activity in Gastric Cancer Cell Lines withFGFR2Amplification

Cited by 36 publications

References 28 publications

Targeting VEGFR and FGFR in head and neck squamous cell carcinoma in vitro

Targeting VEGFR and FGFR in head and neck squamous cell carcinoma in vitro

Evaluation of Fibroblast Growth Factor Receptor 2 Expression, Heterogeneity and Clinical Significance in Gastric Cancer

FGFR2 amplification is predictive of sensitivity to regorafenib in gastric and colorectal cancers in vitro

Contact Info

Product

Resources

About