Overexpression of &lt;i&gt;KLF13&lt;/i&gt; and &lt;i&gt;FGFR3&lt;/i&gt; in Oral Cancer Cells

Henson, Brian J.; Gollin, Susanne M.

doi:10.1159/000308303

Cited by 53 publications

(49 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Translocation events implicating the FGFR1 gene and various fusions of FGFR1 are found in myeloproliferative syndromes (12); chromosomal translocations of FGFR1 or FGFR3 and the transforming acidic coiled-coil genes (TACC1 or TACC3) are oncogenic in glioblastoma multiforme, bladder cancer, head and neck cancer, and lung cancer (13)(14)(15)(16); oncogenic mutations of FGFR2 and FGFR3 are observed in lung squamous cell carcinoma; FGFR2 N549K is observed in 25% of endometrial cancers; FGFR3 t(4;14) alterations are reported in 15-20% of multiple myeloma (17)(18)(19); FGFR4 Y367C mutation in the transmembrane domain drives constitutive activation and enhanced tumorigenic phenotypes in a breast carcinoma cell line (20)(21)(22); and K535 and E550 mutants are reported to activate FGFR4 in rhabdomyosarcoma (23). FGFR amplification is reported in various cancers (24,25): FGFR1 is amplified in colorectal, lung, and renal cell cancers (26,27); FGFR2 is amplified in gastric cancer and colorectal cancer (28,29); FGFR3 is commonly amplified in bladder cancer and also is reported for cervical, oral, and hematological cancers (30)(31)(32); and FGFR4 is amplified in hepatocellular carcinoma, gastric cancer, pancreatic cancer, and ovarian cancer (33)(34)(35)(36)(37). FGFR also is involved in autocrine activation of STAT3 as a positive feedback in many drug-treated cancer cells which are driven by diverse oncogenes such as EGFR, ALK, MET, and KRAS (38).…”

Section: Significancementioning

confidence: 99%

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Li¹,

Wang²,

Tanizaki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

163

132

View full text Add to dashboard Cite

The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.drug discovery | cancer drug resistance | kinase inhibitor | structure-based drug design R eceptor tyrosine kinases (RTKs) serve as critical sensors of extracellular cues that activate a myriad of intracellular signaling pathways to regulate cell state. There are 58 receptor tyrosine kinases in the human genome, and many have been demonstrated to be constitutively activated through amplification or mutation in particular cancers. The signals emanating from these RTKs, such as epidermal growth factor receptor (EGFR), FGF receptor (FGFR), platelet-derived growth factor receptor (PDGFR), protein kinase Kit (KIT), and protein kinase c-Met (MET), have been pharmacologically proven to be essential to the survival of cancers expressing mutant forms of these proteins. However, rapid resistance to monotherapy with first-generation RTK inhibitors has been universally observed. Resistance typically arises from the emergence of cancer cells expressing mutant forms of RTKs that are impervious to the action of first-generation drugs or from the activation of by-pass signaling mechanisms. Resistance can be overcome by developing new inhibitors that target the mutant RTK directly or target bypass signaling mechanisms. Indeed this approach has been deployed succes...

show abstract

Section: Significancementioning

confidence: 99%

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Li¹,

Wang²,

Tanizaki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

163

132

View full text Add to dashboard Cite

show abstract

“…KLF13 is required for the expression of several oncogenes including cyclin D1, which is a known oncogene in oral squamous cell carcinoma (47,49). Furthermore, KLF13 is believed to play a role in cancer, and altered expression of it contributes to tumorigenesis (50–53).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatic identification of candidate genes induced by trichostatin A in BGC-823 gastric cancer cells

Zhang

Yang

et al. 2016

Oncology Letters

View full text Add to dashboard Cite

The aim of the present study was to identify the candidate genes induced by trichostatin A (TSA) in BGC-823 gastric cancer (GC) cells and to explore the possible inhibition mechanism of TSA in GC. Gene expression data were obtained through chip detection, and differentially expressed genes (DEGs) between GC cells treated with TSA and untreated GC cells (control group) were identified. Gene ontology analysis of the DEGs was performed using the database for annotation, visualization and integrated discovery. Then sub-pathway enrichment analysis was performed and a microRNA (miRNA) regulatory network was constructed. We selected 76 DEGs, among which 43 were downregulated genes and 33 were upregulated genes. By sub-pathway enrichment analysis of the DEGs, the propanoate metabolism pathway was selected as the sub-pathway. By constructing a miRNA regulatory network, we identified that DKK1 and KLF13 were the top hub nodes. The propanoate metabolism pathway and the genes DKK1 and KLF13 may play significant roles in the inhibition of GC induced by TSA. These genes may be potential therapeutic targets for GC. However, further experiments are still required to confirm our results.

show abstract

“…Our study, as well as previous publications, found variable expression of various RTKs in HNSCC cells and fibroblasts. 3–8,16–19 Consequently, we choose a treatment agent which targeted multiple RTKs (dovitinib).…”

Section: Discussionmentioning

confidence: 99%

“…3–6 These receptors bind FGF-2 (FGF-basic), which has been found to be elevated in HNSCC specimens. 6 Furthermore, FGF-2 and FGFR-1 expression in tumor associated fibroblast of HNSCC specimens correlate with higher grade, increased incidence of lymph node metastasis and poor prognosis.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of tyrosine receptor kinases in the interactions of head and neck squamous cell carcinoma cells and fibroblasts

Sweeny

Zimmermann

et al. 2012

Oral Oncology

View full text Add to dashboard Cite

Summary Despite treatment advancements, disease-free survival of head and neck squamous cell carcinoma (HNSCC) has not significantly improved. This may be a result of tumor-fibroblasts interactions providing protective pathways for oncogenic cells to resist therapy. Further understanding of these relationships in HNSCC may improve effectiveness of targeted therapies. In this article, we investigated the role of several receptor tyrosine kinases (RTK) in the interactions between HNSCC cells and supporting cells (fibroblasts). Evaluation of HNSCC tumor specimens, cell lines and fibroblasts found variable expression of multiple RTKs (fibroblasts growth factor receptor, platelet derived growth factor receptor and vascular endothelial growth factor receptor) and their ligands, supporting previous theories of paracrine and autocrine signaling within the microenvironment. In a dose-dependent fashion, RTK inhibition reduced proliferation of HNSCC cell lines and fibroblast in vitro. When HNSCC cells were cocultured with fibroblasts, RTK inhibition resulted in a smaller reduction in the proliferation relative to untreated conditions. In vivo, RTK inhibition resulted in significant tumor regression and growth inhibition (p<0.05) and reduced the incidence of regional lymph node metastasis. Effective treatment of HNSCC, therefore, may require inhibition of multiple RTKs in order to adequately inhibit the microenvironment’s various signaling pathways.

show abstract

Overexpression of <i>KLF13</i> and <i>FGFR3</i> in Oral Cancer Cells

Cited by 53 publications

References 68 publications

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Bioinformatic identification of candidate genes induced by trichostatin A in BGC-823 gastric cancer cells

Evaluation of tyrosine receptor kinases in the interactions of head and neck squamous cell carcinoma cells and fibroblasts

Contact Info

Product

Resources

About