Functional roles of fibroblast growth factor receptors (FGFRs) signaling in human cancers

Tiong, Kai Hung; Mah, Li Yen; Leong, Chee‐Onn

doi:10.1007/s10495-013-0886-7

Cited by 152 publications

(136 citation statements)

References 279 publications

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“…These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance. (5,6). The fundamental importance of FGFR to development is well proven by gain-of-function mutations that result in dwarfism in model organisms and in humans (7)(8)(9)(10).…”

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.

169

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.

169

132

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“…Further studies of other polymorphisms in these genes and the expression profile could elicit essential information because FGFR2 is a tumour suppressor gene amplified and overexpressed in 10-15% of breast tumours (Rebbeck et al 2009;Ahmad et al 2012;Tiong et al 2013) and enhanced FGFR expression may not only be due to genetic alterations but also to epigenetic deregulation at transcriptional and post-translational levels.…”

Section: Discussionmentioning

confidence: 99%

“…Their binding induces functional FGFR dimerization and kinase activation by trans-autophoshorylation which activates multiple downstream cellular cascades and responses (Wesche et al 2011;Tiong et al 2013). The cascade involving mitogen-activated protein kinase 1 (MAP3K1), a serine-threonine kinase in the MAP3K family and the STE superfamily, comprises of several steps: activated FGFR kinase trigger stimulation of its intracellular substrates.…”

Section: Introductionmentioning

confidence: 99%

Association of single nucleotide polymorphisms in FGF-RAS/MAP signalling cascade with breast cancer susceptibility

Daňková¹,

Žúbor²,

Grendár³

et al. 2017

gpb

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Abstract. The fibroblast growth factor receptors (FGFRs) and Ras/mitogen activated protein (RAS/ MAP) signalling cascades are the main molecular pathways involved in breast carcinogenesis. This study aims to determine the association between FGF10 (rs4415084 C>T), FGFR2 (rs2981582 C>T) and MAP3K1 (rs889312 A>C) gene polymorphisms and breast cancer, to analyse the discriminative ability of each SNP and to test the accuracy of the predictive breast cancer risk model which includes all SNPs. We conducted a case-control study of 170 women (57.06 ± 11.60 years) with histologically confirmed breast cancer and 146 controls (50.24 ± 10.69 years). High resolution melting (HRM) method with Sanger sequencing validation was used in analyses. We have revealed significant association of FGFR2 and MAP3K1 polymorphisms with breast cancer. The odds ratio of FGFR2 T allele was 1.897 (95% CI 1.231-2.936, p = 0.004) and MAP3K1 C allele 1.804 (95% CI 1.151-2.845, p = 0.012). FGFR2 polymorphism achieved the best discriminative ability (41.95%). The Random Forest algorithm selected FGFR2, MAP3K1 and age as important breast cancer predictors. The accuracy of this prediction model approached moderate accuracy (70%), with 35.9% sensitivity and 88.6% specificity.

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“…Ген Fgf15 мыши имеет человеческий ортолог -ген FGF19, который кодирует белок FGF19, соответствующий Fgf15 мыши, поэтому их называют FGF15/19. В зависимости от функциональных свойств все факторы FGF делят на несколько подсемейств: паракринные (1-10, 16-20, 22); эндокринные, или гормоноподобные (15,19,21,23); и интракринные (11)(12)(13)(14). Секретируемые белки FGF способны индуцировать физиологический эффект в расположенных вблизи клетках-мишенях (паракринные FGF), а также оказывать системное влияние на отдалённые ткани и органы (эндокринные FGF).…”

Section: общая характеристика сигнального пути Fgf/fgfrunclassified

“…В эту группу изменений входят: амплификация локуса с геном, кодирующим FGFR; точковая активирующая мутация; хромосомные транслокации, приводящие к слиянию двух белков; переключение на аутосигнализацию; ослабление отрицательной обратной связи и аберрантный альтернативный сплайсинг [19]. Как уже упоминалось выше, альтернативный сплайсинг домена IgIII (D3) приводит к образованию изоформ IIIa, IIIb и IIIc рецепторов FGFR 1, 2 и 3.…”

Section: сигнальный путь Fgf/fgfr в опухолях поджелудочной железыunclassified

Role of fibroblast growth factors in pancreatic cancer

Gnatenko

Копанцев

2016

BIOMED KHIM

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Факторы роста фибробластов (FGF) -сигнальные молекулы c широким спектром действия, вовлечённые во многие клеточные процессы. FGF играют важную роль не только в органогенезе, но и в канцерогенезе поджелудочной железы. Они относятся к тем факторам, посредством которых происходит потенцирующее взаимодействие между опухолью и окружающей её стромой -ключевым компонентом развития рака поджелудочной железы. Нарушения сигнального пути FGF/FGFR -комплексный процесс, в котором важную роль играют тип и изоформа рецепторов, регулирующих ремоделирующий эффект FGF и последующую активацию данными факторами пролиферации клеток рака поджелудочной железы. Факторы FGF и их рецепторы рассматриваются как потенциальные специфические маркеры и возможные мишени для терапии рака поджелудочной железы.Ключевые слова: ростовые факторы, рак, поджелудочная железа, мастер-гены

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Functional roles of fibroblast growth factor receptors (FGFRs) signaling in human cancers

Cited by 152 publications

References 279 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

Association of single nucleotide polymorphisms in FGF-RAS/MAP signalling cascade with breast cancer susceptibility

Role of fibroblast growth factors in pancreatic cancer

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