FGFR1

Official Full Name

fibroblast growth factor receptor 1

Organism

Homo sapiens

GeneID

2260

Background

The protein encoded by this gene is a member of the fibroblast growth factor receptor (FGFR) family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member binds both acidic and basic fibroblast growth factors and is involved in limb induction. Mutations in this gene have been associated with Pfeiffer syndrome, Jackson-Weiss syndrome, Antley-Bixler syndrome, osteoglophonic dysplasia, and autosomal dominant Kallmann syndrome 2. Chromosomal aberrations involving this gene are associated with stem cell myeloproliferative disorder and stem cell leukemia lymphoma syndrome. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]

Synonyms

CEK; FLG; HH2; OGD; ECCL; FLT2; KAL2; BFGFR; CD331; FGFBR; FLT-2; HBGFR; N-SAM; FGFR-1; HRTFDS; bFGF-R-1;

Bio Chemical Class

Kinase

Protein Sequence

MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAVMTSPLYLEIIIYCTGAFLISCMVGSVIVYKMKSGTKKSDFHSQMAVHKLAKSIPLRRQVTVSADSSASMNSGVLLVRPSRLSSSGTPMLAGVSEYELPEDPRWELPRDRLVLGKPLGEGCFGQVVLAEAIGLDKDKPNRVTKVAVKMLKSDATEKDLSDLISEMEMMKMIGKHKNIINLLGACTQDGPLYVIVEYASKGNLREYLQARRPPGLEYCYNPSHNPEEQLSSKDLVSCAYQVARGMEYLASKKCIHRDLAARNVLVTEDNVMKIADFGLARDIHHIDYYKKTTNGRLPVKWMAPEALFDRIYTHQSDVWSFGVLLWEIFTLGGSPYPGVPVEELFKLLKEGHRMDKPSNCTNELYMMMRDCWHAVPSQRPTFKQLVEDLDRIVALTSNQEYLDLSMPLDQYSPSFPDTRSSTCSSGEDSVFSHEPLPEEPCLPRHPAQLANGGLKRR

Open

Disease

Acute diabete complication, Acute myeloid leukaemia, Alzheimer disease, Bladder cancer, Breast cancer, Chronic arterial occlusive disease, Colorectal cancer, Coronary atherosclerosis, Endometrial cancer, Epidermal dysplasias, Gram-positive bacterial infection, Idiopathic interstitial pneumonitis, Liver cancer, Lung cancer, Multiple myeloma, Myelodysplastic syndrome, Myeloproliferative neoplasm, Non-alcoholic fatty liver disease, Oesophagitis, Ovarian cancer, Peritoneal cancer, Retina cancer, Solid tumour/cancer, Stomach cancer, Thrombocytopenia, Type 2 diabetes mellitus

Approved Drug

3 +

Clinical Trial Drug

14 +

Discontinued Drug

1 +

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Detailed Information

The fibroblast growth factor receptor type 1 gene (FGFR1) is one of the most commonly amplified genes in human cancer. The fibroblast growth factor receptor (FGFR) tyrosine kinase family is comprised of four kinases, FGFR1, 2, 3, and 4, that play important role in development, and have been shown to be targets for deregulation by either amplification, point mutation, or translocation. FGFRs, as members of the receptor tyrosine kinase (RTK) family, are known to signal, after ligand binding and receptor dimerization, from the cell membrane as well as from endosomal compartments. Signal transduction, primarily through the MAPK pathway but also acting via phosphoinositide 3-kinase (PI3K), STATs, and PLC-γ, leads to activation of several known target genes (e.g., CyclinD1 and PEA3) to modulate cell behavior. In addition to these well-studied signaling pathways, there is a growing body of evidence showing that full-length FGFRs, and FGFR1 in particular, can be targeted to the nucleus.

The FGFR signaling pathway is implicated in a wide range of pathologies, most notably cancer, yet its efficient targeting is proving challenging to the pharmaceutical industry, partly because FGFR signaling is fundamental to so many normal biological processes. More and more data has suggested that targeting FGFR1 might represent a novel therapeutic approach in blocking cancer invasion. Amplification or activation of FGFR1 has been reported in oral squamous carcinoma, esophageal squamous cell carcinomas, ovarian cancer, prostate cancer, bladder cancer, and lung cancer. Consistent with this, a pan-FGFR tyrosine kinase inhibitor has been shown to block tumor proliferation in a subset of non-small cell lung cancer (NSCLC) cell lines with activated FGFR signaling but has no effect on cells that do not activate the pathway. FGFR1 has been identified as the driver event in breast carcinomas and NSCLC, especially squamous cell lung carcinomas, harboring similar amplifications of the 8p11 chromosomal segment.

FGFR1 and lung cancer

A recent report identifies FGFR1 as a potential therapeutic target in NSCLC, where 8p11-12 amplification is common, suggesting that high levels of expression of FGFR1 may contribute to tumorigenesis or progression in NSCLC. As FGFR1 amplification has been reported in other tumor types, it may be the case that FGFR1 inhibition will be a successful therapeutic strategy in a variety of settings. Because some FGFR kinase inhibitors are now in clinical trials, including dovitinib, brivanib, BIBF 1120, and SU-6668, it could be useful to test these inhibitors on NSCLC patients bearing focal FGFR1 amplification. Given that amplification alone will not always predict sensitivity to FGFR1 inhibition, additional work is needed to fully characterize the genetic alterations involved in NSCLC carcinogenesis and dependency on FGFR1.

FGFR1 and breast cancer

Amplification of FGFR1 occurs in ∼10% of breast cancers and is associated with poor prognosis. Breast cancer cell lines with FGFR1 overexpression show enhanced ligand-dependent signaling, with increased activation of the mitogen-activated protein kinase and phosphoinositide 3-kinase–AKT signaling pathways in response to FGF2, but also show basal ligand-independent signaling, and are dependent on FGFR signaling for anchorage-independent growth. Moreover, some studies show that amplified cancers have a high proliferative rate assessed by Ki67 staining and that FGFR1 amplification is found in 16% to 27% of luminal B–type breast cancers. The amplification and overexpression of FGFR1 may be a major contributor to poor prognosis in luminal-type breast cancers, driving anchorage-independent proliferation and endocrine therapy resistance. In short, FGFR1 amplification is one of the major drivers of highly proliferative, poor-prognosis, luminal B subtype, ER-positive breast cancers. This provides a strong rationale for the investigation of drugs that target FGFR1 in breast cancer, particularly in combination with endocrine therapy.

References:

Chioni A M, Grose R. FGFR1 cleavage and nuclear translocation regulates breast cancer cell behavior. J Cell Biol, 2012, 197(6): 801-817.
Yang F, et al. FGFR1 Is Essential for Prostate Cancer Progression and Metastasis. Cancer Research, 2013, 73(12):3716-3724.
Brewer J R, et al. Fgfr1 regulates development through the combinatorial use of signaling proteins. Genes & Development, 2015.
Dutt A, et al. Inhibitor-Sensitive FGFR1 Amplification in Human Non- Small Cell Lung Cancer. PLoS ONE, 2011, 6(6):e20351.
Turner N, et al. FGFR1 Amplification Drives Endocrine Therapy Resistance and Is a Therapeutic Target in Breast Cancer. Cancer Research, 2010, 70(5):2085-2094.

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