Klotho-beta overexpression as a novel target for suppressing proliferation and fibroblast growth factor receptor-4 signaling in hepatocellular carcinoma

Poh, Weijie; Wong, Winnie; Ong, Huimin; Aung, Myat Oo; Lim, Seng Gee; Chua, Boon Tin; Ho, Han Kiat

doi:10.1186/1476-4598-11-14

Cited by 60 publications

(70 citation statements)

References 34 publications

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“…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.

159

132

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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...

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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.

159

132

View full text Add to dashboard Cite

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“…Amplifications of FGF19 in HCC have been reported in several genomics studies. 1,3,4 Recent studies have demonstrated that FGF19 plays key roles in hepatocarcinogenesis. 5 Genetic aberrations in FGF21 have not been reported in liver cancer genomics studies.…”

Section: Replymentioning

confidence: 99%

“…2 Interestingly, FGF21 was overexpressed in HCC. 1,3,4 It should be very interesting to assess if, from the data set of genome-wide analysis, HCC samples in which FGF19 high copy amplifications overlap with copy number variations or single mutations localized at 19q13.33 containing the FGF21 gene may emerge. This could be very relevant to understanding if an anti-FGF19 strategy may be potentially sufficient as a therapeutic approach.…”

mentioning

confidence: 99%

Targeting FGF19 binding to its receptor system: A novel therapeutic approach for hepatocellular carcinoma

et al. 2015

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“…Circulating NPCs represent a subpopulation of activated neutrophils primed for adhesion, phagocytosis, and intracellular killing, 3 which protects against microbial invasion, but paradoxically induces endothelial dysfunction, bystander damage, and end-organ dysfunction. 4 In summary, neutrophil-platelet interactions appear, at least in vitro, to contribute toward neutrophil dysfunction in cirrhosis. Therefore, administration of a platelet transfusion before an invasive procedure or during bleeding episodes in patients with cirrhosis could be detrimental by promoting neutrophil activation and increased NPC formation.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Could abnormal neutrophil‐platelet interactions and complex formation contribute to oxidative stress and organ failure in cirrhosis?

et al. 2015

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Susceptibility to developing infection is well recognized in cirrhosis: circulating neutrophil dysfunction, including excessive production of reactive oxygen species (ROS), is a major contributor to innate immune paresis, development of multiorgan failure, and survival.1 Platelets also play a key role in modulating inflammation by interacting with neutrophils, secreting inflammatory mediators, and influencing phagocytosis/apoptosis.2 Here, we report on the results of a pilot study that examined neutrophil-platelet interactions in patients with cirrhosis and characterized responses when their neutrophils were exposed to healthy platelets simulating platelet transfusion.Neutrophil-platelet interactions were characterized in 10 patients with stable advanced cirrhosis (9:1 male/female; mean age: 56.5 years; mean Child-Pugh score: 10) in a paired crossover study with 10 healthy controls (HCs). Neutrophils and platelets were isolated separately and incubated in zero, 50:1, and 100:1 platelet: neutrophil ratios. Neutrophils were stained with anti-CD16-PE and anti-CD11b-APC-Cy7 (macrophage-1 antigen) and analyzed using flow cytometry. Platelets were stained with anti-CD41a-APC (glycoprotein IIb/IIIa), and neutrophil-platelet complexes (NPCs) were identified as staining for CD11b/CD16/CD41a. Neutrophils were stimulated with phorbol myristate acetate, which induces ROS production, which was quantified by conversion of dihydrorhodamine-123 to rhodamine-123. Both the amount of ROS production and the number of neutrophils undergoing oxidative burst were measured.After stimulation, samples incubated with healthy platelets had fewer neutrophils undergoing oxidative burst, compared to cirrhotic platelets (P < 0.05, 50:1; P < 0.01, 100:1 ratios; Fig. 1A). The addition of healthy platelets also corresponded with a significant increase in NPCs (P < 0.05, 100:1 ratio; Fig. 1B). Neutrophils that were part of an NPC demonstrated a 3-fold increase in CD11b expression over the background population of neutrophils (P < 0.01). Circulating NPCs represent a subpopulation of activated neutrophils primed for adhesion, phagocytosis, and intracellular killing, 3 which protects against microbial invasion, but paradoxically induces endothelial dysfunction, bystander damage, and end-organ dysfunction. 4In summary, neutrophil-platelet interactions appear, at least in vitro, to contribute toward neutrophil dysfunction in cirrhosis. Therefore, administration of a platelet transfusion before an invasive procedure or during bleeding episodes in patients with cirrhosis could be detrimental by promoting neutrophil activation and increased NPC formation. Further studies are now warranted to assess the in vivo consequences of administration of platelet transfusions in patients with cirrhosis. Fig. 1. Graphs demonstrating the (A) reduction in the number of neutrophils undergoing oxidative burst (OB) with the addition of healthy and cirrhotic platelets and (B) formation of neutrophil-platelet complexes following addition of platelets. Ratios (50:1 and 100:...

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Klotho-beta overexpression as a novel target for suppressing proliferation and fibroblast growth factor receptor-4 signaling in hepatocellular carcinoma

Cited by 60 publications

References 34 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

Targeting FGF19 binding to its receptor system: A novel therapeutic approach for hepatocellular carcinoma

Could abnormal neutrophil‐platelet interactions and complex formation contribute to oxidative stress and organ failure in cirrhosis?

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