Molecule Information

General Information of the Molecule (ID: Mol00371)

• Name: Fibroblast growth factor receptor 1 (FGFR1) ,Homo sapiens
• Molecule Type: Protein
• Gene Name: FGFR1
• Gene ID: 2260
• Location: chr8:38400215-38468834[-]
• Sequence:
  MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDD
  VQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSD
  ALPSSEDDDDDDDSSSEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPS
  SGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSIN
  HTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKI
  GPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLE
  ALEERPAVMTSPLYLEIIIYCTGAFLISCMVGSVIVYKMKSGTKKSDFHSQMAVHKLAKS
  IPLRRQVTVSADSSASMNSGVLLVRPSRLSSSGTPMLAGVSEYELPEDPRWELPRDRLVL
  GKPLGEGCFGQVVLAEAIGLDKDKPNRVTKVAVKMLKSDATEKDLSDLISEMEMMKMIGK
  HKNIINLLGACTQDGPLYVIVEYASKGNLREYLQARRPPGLEYCYNPSHNPEEQLSSKDL
  VSCAYQVARGMEYLASKKCIHRDLAARNVLVTEDNVMKIADFGLARDIHHIDYYKKTTNG
  RLPVKWMAPEALFDRIYTHQSDVWSFGVLLWEIFTLGGSPYPGVPVEELFKLLKEGHRMD
  KPSNCTNELYMMMRDCWHAVPSQRPTFKQLVEDLDRIVALTSNQEYLDLSMPLDQYSPSF
  PDTRSSTCSSGEDSVFSHEPLPEEPCLPRHPAQLANGGLKRR
• Function: Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration. Required for normal mesoderm patterning and correct axial organization during embryonic development, normal skeletogenesis and normal development of the gonadotropin-releasing hormone (GnRH) neuronal system. Phosphorylates PLCG1, FRS2, GAB1 and SHB. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes phosphorylation of SHC1, STAT1 and PTPN11/SHP2. In the nucleus, enhances RPS6KA1 and CREB1 activity and contributes to the regulation of transcription. FGFR1 signaling is down-regulated by IL17RD/SEF, and by FGFR1 ubiquitination, internalization and degradation.
• Uniprot ID: FGFR1_HUMAN
• Ensembl ID: ENSG00000077782
• 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

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 3 drug(s) in total

Erlotinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Pancreatic cancer [1]

• Sensitive Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Sensitive Drug: Erlotinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: FGF/FGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: MIA PaCa-2 cells; Pancreas; Homo sapiens (Human); CVCL_0428
• In Vitro Model: SW1990 cells; Pancreas; Homo sapiens (Human); CVCL_1723
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-497 suppressed cells proliferation, decreased the percentage of S phase cells, re-sensitized cells to gemcitabine and erlotinib, and attenuated migration and invasion capacities. Furthermore, fibroblast growth factor 2 and fibroblast growth factor receptor 1 were confirmed as miR-497 targets. Overexpression of miR-497 inhibited tumor growth in vivo. Additionally, miR-497 expression was significantly downregulated in pancreatic cancer tissues compared with tumor-adjacent samples. Low expression of miR-497 was an independent adverse prognostic factor of pancreatic cancer. miR-497 plays a role in modulating the malignant phenotype and chemosensitivity of pancreatic cancer cells by directly inhibition of FGF2 and FGFR1 expression.

Gemcitabine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Pancreatic cancer [1]

• Sensitive Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Sensitive Drug: Gemcitabine
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: FGF/FGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: MIA PaCa-2 cells; Pancreas; Homo sapiens (Human); CVCL_0428
• In Vitro Model: SW1990 cells; Pancreas; Homo sapiens (Human); CVCL_1723
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-497 suppressed cells proliferation, decreased the percentage of S phase cells, re-sensitized cells to gemcitabine and erlotinib, and attenuated migration and invasion capacities. Furthermore, fibroblast growth factor 2 and fibroblast growth factor receptor 1 were confirmed as miR-497 targets. Overexpression of miR-497 inhibited tumor growth in vivo. Additionally, miR-497 expression was significantly downregulated in pancreatic cancer tissues compared with tumor-adjacent samples. Low expression of miR-497 was an independent adverse prognostic factor of pancreatic cancer. miR-497 plays a role in modulating the malignant phenotype and chemosensitivity of pancreatic cancer cells by directly inhibition of FGF2 and FGFR1 expression.

Infigratinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Intrahepatic cholangiocarcinoma [2]

• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Resistant Drug: Infigratinib
• Molecule Alteration: Structural variation; Amplification
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MET signalling pathway; Activation; hsa04020
• Cell Pathway Regulation: ERK/MAPK signaling pathway; Activation; hsa04210
• In Vitro Model: DMS114 cells; Lung; Homo sapiens (Human); CVCL_1174
• Mechanism Description: Upregulation of the MET signalling pathway leading to re-activation of the ERK/MAPK pathway was observed in conjunction with the development of resistance to infigratinib in FGFR1-amplified DMS114 lung cancer cells.

Disease Class: Intrahepatic cholangiocarcinoma [2]

• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Resistant Drug: Infigratinib
• Molecule Alteration: Structural variation; Amplification
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MET signalling pathway; Activation; hsa04020
• Cell Pathway Regulation: ERK/MAPK signaling pathway; Activation; hsa04210
• In Vitro Model: DMS114 cells; Lung; Homo sapiens (Human); CVCL_1174
• Mechanism Description: Upregulation of the MET signalling pathway leading to re-activation of the ERK/MAPK pathway was observed in conjunction with the development of resistance to infigratinib in FGFR1-amplified DMS114 lung cancer cells.

Clinical Trial Drug(s) 2 drug(s) in total

AZD-4547

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [3]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: AZD-4547
• Molecule Alteration: Missense mutation; p.V561M (c.1681G>A)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: L6 cells; Skeletal muscle; Rattus norvegicus (Rat); CVCL_0385
• In Vitro Model: H1581 cells; Lung; Homo sapiens (Human); CVCL_1479
• Experiment for Molecule Alteration: SDS-PAGE assay
• Experiment for Drug Resistance: Transwell migration assay; Matrigel invasion assay; Proliferation assay; MTT assay
• Mechanism Description: The V561M mutation biases cells towards a more mesenchymal phenotype, including increased levels of proliferation, migration, invasion and anchorage-independent growth, which was confirmed using CyTOF, a novel single cell analysis tool. Using shRNA knockdown, loss of STAT3 restored sensitivity of cancer cells expressing V561M FGFR1 to AZD4547. Thus, the data demonstrate that combination therapies including FGFR and STAT3 may overcome V561M FGFR1 driven drug resistance in the clinic.

PRN1371

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [4]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: PRN1371
• Molecule Alteration: Missense mutation; p.V561M (c.1681G>A)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: FGF/FGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: RT112 cells; Bladder; Homo sapiens (Human); CVCL_1670
• In Vitro Model: AN3CA cells; Ovary; Homo sapiens (Human); CVCL_0028
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: SNU878 cells; Liver; Homo sapiens (Human); CVCL_5102
• In Vitro Model: SNU16 cells; Ascites; Homo sapiens (Human); CVCL_0076
• In Vitro Model: OPM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1625
• In Vitro Model: LI7 cells; Liver; Homo sapiens (Human); CVCL_3840
• In Vitro Model: JHH7 cells; Liver; Homo sapiens (Human); CVCL_2805
• In Vivo Model: Nude mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: PRN1371 exhibits potent and durable pathway inhibition, and robust antiproliferative activity. PRN1371 demonstrates prolonged FGFR inhibition in vivo.

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

FIIN-1

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Solid tumour/cancer [5]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: FIIN-1
• Molecule Alteration: Missense mutation; p.V561M (c.1681G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Drug Resistance: CellTiter-Glo Luminescent Cell Viability Assay
• Mechanism Description: The missense mutation p.V561M (c.1681G>A) in gene FGFR1 cause the sensitivity of FIIN-1 by aberration of the drug's therapeutic target

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Pancreatic cancer [ICD-11: 2C10]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Pancreas
• The Specified Disease: Pancreatic cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.09E-02; Fold-change: -5.79E-01; Z-score: -8.25E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.51E-10; Fold-change: -7.65E-01; Z-score: -9.93E-01

Liver cancer [ICD-11: 2C12]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Liver
• The Specified Disease: Liver cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.18E-03; Fold-change: -1.21E-01; Z-score: -5.86E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 3.61E-03; Fold-change: -8.13E-02; Z-score: -2.77E-01
• The Expression Level of Disease Section Compare with the Other Disease Section: p-value: 5.22E-01; Fold-change: -7.72E-02; Z-score: -4.71E-01

Lung cancer [ICD-11: 2C25]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Lung
• The Specified Disease: Lung cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.41E-12; Fold-change: -2.79E-01; Z-score: -8.43E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 9.04E-11; Fold-change: -3.59E-01; Z-score: -8.30E-01

References

• Ref 1: MiR-497 downregulation contributes to the malignancy of pancreatic cancer and associates with a poor prognosis. Oncotarget. 2014 Aug 30;5(16):6983-93. doi: 10.18632/oncotarget.2184.
• Ref 2: Fibroblast growth factor receptors in cancer: genetic alterations, diagnostics, therapeutic targets and mechanisms of resistance .Br J Cancer. 2021 Mar;124(5):880-892. doi: 10.1038/s41416-020-01157-0. Epub 2020 Dec 3. 10.1038/s41416-020-01157-0
• Ref 3: The FGFR1 V561M Gatekeeper Mutation Drives AZD4547 Resistance through STAT3 Activation and EMTMol Cancer Res. 2019 Feb;17(2):532-543. doi: 10.1158/1541-7786.MCR-18-0429. Epub 2018 Sep 26.
• Ref 4: The Irreversible Covalent Fibroblast Growth Factor Receptor Inhibitor PRN1371 Exhibits Sustained Inhibition of FGFR after Drug ClearanceMol Cancer Ther. 2017 Dec;16(12):2668-2676. doi: 10.1158/1535-7163.MCT-17-0309. Epub 2017 Oct 4.
• Ref 5: A structure-guided approach to creating covalent FGFR inhibitorsChem Biol. 2010 Mar 26;17(3):285-95. doi: 10.1016/j.chembiol.2010.02.007.