FGFR2 alterations in endometrial carcinoma

Gatius, Sònia; Velasco, Ana; Azueta, Ainara; Santacana, Maria; Pallarés, Judit; Valls, Joan; Dolcet, Xavier; Prat, Jaime; Matías‐Guiu, Xavier

doi:10.1038/modpathol.2011.110

Cited by 61 publications

(53 citation statements)

References 33 publications

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“…Endometrial tumors are characterized by heterogeneity of genetic alterations, including defects in FGFR2 expression. Indeed, several studies have identified FGFR2 mutations in a frequency of 6.5% to 12% (8)(9)(10)(11). However, some authors consider that these frequencies may be an underestimation because studies of frequency mutation of FGFR2 in endometrial carcinomas have only included patients with primary cancers (19).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, it has become clearer that the response to target inhibition is also affected in a context-dependent manner wherein these mutations occur. We have previously demonstrated that FGFR2 expression in endometrial carcinomas is significantly associated with increased ER and PR (11). ER-and PR-positive expression in endometrial carcinomas have better outcomes and hypothetically are likely to respond better to hormonal therapy.…”

Section: Discussionmentioning

confidence: 99%

“…7). Recently, some investigators have suggested that alterations in fibroblast growth factor receptor 2 (FGFR2) could be added to the molecular-specific features of endometrioid endometrial carcinomas with a frequency of 6.5% to 12% (8)(9)(10)(11). Moreover, Pollock and colleagues have recently reported that presence of FGFR2 mutations is significantly associated with shorter disease-free survival (12).…”

Section: Introductionmentioning

confidence: 99%

“…Activation of FGFR triggers multiple antiapoptotic pathways, including peritoneal lymphocytes g, phosphoinositide 3-kinase (PI3K)-AKT, mitogen-activated protein kinase (MAPK), and STATs. This pro-survival effect has also been linked to resistance to chemotherapy (11,15). However, one of the predominant signaling pathway-activated downstream of FGFR is RAS-MAPK.…”

Section: Introductionmentioning

confidence: 99%

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Combinatorial Therapy Using Dovitinib and ICI182.780 (Fulvestrant) Blocks Tumoral Activity of Endometrial Cancer Cells

Eritja

Domingo

Dosil

et al. 2014

Molecular Cancer Therapeutics

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Mutations in fibroblast growth factor receptor 2 (FGFR2) have been recently described as a molecularspecific feature in endometrial carcinomas and the presence of activated FGFR2 mutations is associated with poor prognosis. For that reason, inhibition of FGFR2 could be a therapeutic target in the treatment of endometriod carcinomas. In this work, we investigated the antitumoral activity of dovitinib (a multiple kinase inhibitor) in human endometrial cancer cell (ECC) lines. We found that dovitinib caused cell growth arrest, loss of clonogenic growth, and cell-cycle arrest in FGFR2-mutated ECCs in in vitro and in vivo experiments. Next, we investigated the mechanistic basis of dovitinib effects. We could determine that dovitinib modified expression levels of well-known key cell-cycle regulatory proteins that induce cellular senescence. To further investigate the role of dovitinib, we analyzed its effect on estrogen receptor a (ER-a) expression. Surprisingly, we discovered that dovitinib enhances ER-a expression in FGFR2-mutant ECCs. Because blocking one signaling pathway is often not sufficient to cause total tumor regression and the effectiveness of individual inhibitors is often short-lived, we examined the impact of targeting FGFR2 with dovitinib in combination with a selective ER antagonist, fulvestrant (ICI182.780). Combination of dovitinib plus ICI182.780 resulted in a significantly higher inhibition of cell growth than dovitinib treatment alone. These findings suggest that combinatory therapies using dovitinib plus ICI182.780 treatment can be truly effective in patients with endometrial carcinomas carrying FGFR2 mutations. Mol Cancer Ther; 13(4); 776-87. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Combinatorial Therapy Using Dovitinib and ICI182.780 (Fulvestrant) Blocks Tumoral Activity of Endometrial Cancer Cells

Eritja

Domingo

Dosil

et al. 2014

Molecular Cancer Therapeutics

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“…Activation of FGFR-dependent signaling pathways can stimulate tumor initiation, progression, and resistance to therapy. 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).…”

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.

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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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Endometrial Cancer

Reventós

Colás

Martı́nez

et al. 2013

Encyclopedia of Life Sciences

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Endometrial cancer is the most common malignancy of the female genital tract in the US. Immunohistochemistry and genomic studies have led to key insights into the pathogenesis of endometrial carcinoma and have provided a genetic basis for the current dualistic classification of this common malignancy. This classification has been challenged by the recent The Cancer Genome Atlas study, which has pursued a molecular classification that permits classification of all endometrial cancer tumours. Key Concepts: Dualistic classification is the most valid tool to categorise endometrial carcinomas since 1983. Type‐I endometrial cancers are mostly oestrogen dependent. They are low‐grade and low‐stage tumours and present slow evolution and better prognosis than type‐II tumours. Type‐II endometrial cancers are not dependent on hormones. They are high‐grade and aggressive tumours. Type‐I is composed of endometrioid tumours, whereas type‐II is mostly composed of serous histologies and other minor subtypes. Precursor lesions of type‐I and type‐II carcinomas are hyperplasia and intraepithelial carcinoma, respectively. The most common alterations identified in type‐I carcinomas include PTEN , PIK3CA , CTNNB1 , KRAS , FGFR2 and SPRY‐2 mutations and microsatellite instability. The mutated genes identified in type‐II carcinomas include TP53 , PIK3CA , PPP2R1A , Her2/neu , E‐cadherin , CCNE1 and BRCA1 , among others. High‐grade tumours and tumours with mix histologies are difficult to allocate in the dualistic model as they present overlapping or combined morphologic and molecular characteristics from both types. TCGA molecular classification permits the categorisation of all endometrial tumours into 4 categories: POLE ultramutated, MSI hypermutated, copy number low and copy number high. More studies are needed in order to validate the usefulness of the recent molecular classification.

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FGFR2 alterations in endometrial carcinoma

Cited by 61 publications

References 33 publications

Combinatorial Therapy Using Dovitinib and ICI182.780 (Fulvestrant) Blocks Tumoral Activity of Endometrial Cancer Cells

Combinatorial Therapy Using Dovitinib and ICI182.780 (Fulvestrant) Blocks Tumoral Activity of Endometrial Cancer Cells

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

Endometrial Cancer

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