Molecule Information

General Information of the Molecule (ID: Mol04333)

• Name: Fibroblast growth factor receptor 1 (FGFR1) ,Homo sapiens
• Synonyms: Basic fibroblast growth factor receptor 1; Fms-like tyrosine kinase 2; N-sam; Proto-oncogene c-Fgr; CD_antigen=CD331
• Molecule Type: Protein
• Gene Name: FGFR1
• Gene ID: 2260
• Sequence:
  MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDD
  VQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVS
  D ALPSSEDDDDDDDSSSEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKC
  PS SGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYG
  SIN HTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVN
  GSKI GPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAW
  LTVLE ALEERPAVMTSPLYLEIIIYCTGAFLISCMVGSVIVYKMKSGTKKSDFHSQMAV
  HKLAKS IPLRRQVTVSADSSASMNSGVLLVRPSRLSSSGTPMLAGVSEYELPEDPRWEL
  PRDRLVL GKPLGEGCFGQVVLAEAIGLDKDKPNRVTKVAVKMLKSDATEKDLSDLISEM
  EMMKMIGK HKNIINLLGACTQDGPLYVIVEYASKGNLREYLQARRPPGLEYCYNPSHNP
  EEQLSSKDL VSCAYQVARGMEYLASKKCIHRDLAARNVLVTEDNVMKIADFGLARDIHH
  IDYYKKTTNG RLPVKWMAPEALFDRIYTHQSDVWSFGVLLWEIFTLGGSPYPGVPVEEL
  FKLLKEGHRMD KPSNCTNELYMMMRDCWHAVPSQRPTFKQLVEDLDRIVALTSNQEYLD
  LSMPLDQYSPSF PDTRSSTCSSGEDSVFSHEPLPEEPCLPRHPAQLANGGLKRR
• Function: Tyrosine-protein kinase that acts as a cell-surface receptorfor fibroblast growth factors and plays an essential role in theregulation of embryonic development, cell proliferation,differentiation and migration. Required for normal mesoderm patterningand correct axial organization during embryonic development, normalskeletogenesis and normal development of the gonadotropin-releasinghormone neuronal system. Phosphorylates PLCG1, FRS2, GAB1 andSHB. Ligand binding leads to the activation of several signalingcascades. Activation of PLCG1 leads to the production of the cellularsignaling molecules diacylglycerol and inositol 1,4,5-trisphosphate.Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 andSOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and theMAP kinase signaling pathway, as well as of the AKT1 signaling pathway.Promotes phosphorylation of SHC1, STAT1 and PTPN11/SHP2. In thenucleus, enhances RPS6KA1 and CREB1 activity and contributes to theregulation of transcription. FGFR1 signaling is down-regulated byIL17RD/SEF, and by FGFR1 ubiquitination, internalization anddegradation. {ECO:0000250|UniProtKB:P16092,ECO:0000269|PubMed:10830168, ECO:0000269|PubMed:11353842,ECO:0000269|PubMed:12181353, ECO:0000269|PubMed:1379697,ECO:0000269|PubMed:1379698, ECO:0000269|PubMed:15117958,ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17311277,ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:18480409,ECO:0000269|PubMed:19224897, ECO:0000269|PubMed:19261810,ECO:0000269|PubMed:19665973, ECO:0000269|PubMed:20133753,ECO:0000269|PubMed:20139426, ECO:0000269|PubMed:21765395,ECO:0000269|PubMed:8622701, ECO:0000269|PubMed:8663044}.
• Uniprot ID: FGFR1_HUMAN
• Ensembl ID: ENSG0000007778223
• HGNC ID: HGNC:3688

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Imatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Gastrointestinal stromal tumor [ICD-11: 2B5B.0] [1]

• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: FGFR signaling pathway; Activation; hsa01521
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vitro Model: GIST T1 cells; Pleural effusion; Homo sapiens (Human); CVCL_4976
• In Vivo Model: Nu/nu famale mice model; Mus musculus
• Experiment for Molecule Alteration: Western blot assay; RNA extraction assay; RT-qPCR; DNA sequencing assay
• Experiment for Drug Resistance: Cellular survival MTS-based assay; Real-Time monitoring of cell proliferation assay; Immunofluorescence staining assay; Colony formation assay
• Mechanism Description: We show here that long-term culture of IM-resistant GISTs (GIST-R1) with IM substantially down-regulates KIT expression and induces activation of the FGFR-signaling cascade, evidenced by increased expression of total and phosphorylated forms of FGFR1 and 2, FGF-2, and FRS-2, the well-known adaptor protein of the FGF-signaling cascade. This resulted in activation of both AKT- and MAPK-signaling pathways shown on mRNA and protein levels, and rendered cancer cells highly sensitive to pan-FGFR-inhibitors (BGJ 398, AZD 4547, and TAS-120). Indeed, we observed a significant decrease of IC50 values for BGJ 398 in the GIST subclone (GIST-R2) derived from GIST-R1 cells continuously treated with IM for up to 12 months. An increased sensitivity of GIST-R2 cells to FGFR inhibition was also revealed on the xenograft models, illustrating a substantial (>70%) decrease in tumor size in BGJ 398-treated animals when treated with this pan-FGFR inhibitor. Similarly, an increased intra-tumoral apoptosis as detected by immunohistochemical (IHC)-staining for cleaved caspase-3 on day 5 of the treatment was found. As expected, both BGJ 398 and IM used alone lacked the pro-apoptotic and growth-inhibitory activities on GIST-R1 xenografts, thereby revealing their resistance to these TKis when used alone. Important, the knockdown of FGFR2, and, in much less content, FGF-2, abrogated BGJ 398's activity against GIST-R2 cells both in vitro and in vivo, thereby illustrating the FGF-2/FGFR2-signaling axis in IM-resistant GISTs as a primary molecular target for this RTKi. Collectively, our data illustrates that continuous inhibition of KIT signaling in IM-resistant GISTs lacking secondary KIT mutations induced clonal heterogeneity of GISTs and resulted in accumulation of cancer cells with overexpressed FGF-2 and FGFR1/2, thereby leading to activation of FGFR-signaling. This in turn rendered these cells extremely sensitive to the pan-FGFR inhibitors used in combination with IM, or even alone, and suggests a rationale to re-evaluate the effectiveness of FGFR-inhibitors in order to improve the second-line therapeutic strategies for selected subgroups of GIST patients (e.g., IM-resistant GISTs lacking secondary KIT mutations and exhibiting the activation of the FGFR-signaling pathway).

References

• Ref 1: Unraveling the Mechanisms of Sensitivity to Anti-FGF Therapies in Imatinib-Resistant Gastrointestinal Stromal Tumors (GIST) Lacking Secondary KIT Mutations. Cancers (Basel). 2023 Nov 9;15(22):5354.