Molecule Information

General Information of the Molecule (ID: Mol01837)

• Name: Fibroblast growth factor receptor 4 (FGFR4) ,Homo sapiens
• Synonyms: Fibroblast growth factor receptor 4; FGFR-4; CD antigen CD334; JTK2; TKF
• Molecule Type: Protein
• Gene Name: FGFR4
• Gene ID: 2264
• Location: chr5:177,086,905-177,098,144[+]
• Sequence:
  MRLLLALLGVLLSVPGPPVLSLEASEEVELEPCLAPSLEQQEQELTVALGQPVRLCCGRA
  ERGGHWYKEGSRLAPAGRVRGWRGRLEIASFLPEDAGRYLCLARGSMIVLQNLTLITGDS
  LTSSNDDEDPKSHRDPSNRHSYPQQAPYWTHPQRMEKKLHAVPAGNTVKFRCPAAGNPTP
  TIRWLKDGQAFHGENRIGGIRLRHQHWSLVMESVVPSDRGTYTCLVENAVGSIRYNYLLD
  VLERSPHRPILQAGLPANTTAVVGSDVELLCKVYSDAQPHIQWLKHIVINGSSFGADGFP
  YVQVLKTADINSSEVEVLYLRNVSAEDAGEYTCLAGNSIGLSYQSAWLTVLPEEDPTWTA
  AAPEARYTDIILYASGSLALAVLLLLAGLYRGQALHGRHPRPPATVQKLSRFPLARQFSL
  ESGSSGKSSSSLVRGVRLSSSGPALLAGLVSLDLPLDPLWEFPRDRLVLGKPLGEGCFGQ
  VVRAEAFGMDPARPDQASTVAVKMLKDNASDKDLADLVSEMEVMKLIGRHKNIINLLGVC
  TQEGPLYVIVECAAKGNLREFLRARRPPGPDLSPDGPRSSEGPLSFPVLVSCAYQVARGM
  QYLESRKCIHRDLAARNVLVTEDNVMKIADFGLARGVHHIDYYKKTSNGRLPVKWMAPEA
  LFDRVYTHQSDVWSFGILLWEIFTLGGSPYPGIPVEELFSLLREGHRMDRPPHCPPELYG
  LMRECWHAAPSQRPTFKQLVEALDKVLLAVSEEYLDLRLTFGPYSPSGGDASSTCSSSDS
  VFSHDPLPLGSSSFPFGSGVQT
• Function: Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration, and in regulation of lipid metabolism, bile acid biosynthesis, glucose uptake, vitamin D metabolism and phosphate homeostasis. Required for normal down-regulation of the expression of CYP7A1, the rate-limiting enzyme in bile acid synthesis, in response to FGF19. Phosphorylates PLCG1 and FRS2. 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 SRC-dependent phosphorylation of the matrix protease MMP14 and its lysosomal degradation. FGFR4 signaling is down-regulated by receptor internalization and degradation; MMP14 promotes internalization and degradation of FGFR4. Mutations that lead to constitutive kinase activation or impair normal FGFR4 inactivation lead to aberrant signaling.
• Uniprot ID: FGFR4_HUMAN
• Ensembl ID: ENSG00000160867
• HGNC ID: HGNC:3691

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

Drug Resistance Data Categorized by Drug

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

Erdafitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Breast cancer [1]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Erdafitinib
• Molecule Alteration: Missense mutation; p.V550M
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: The mutations V550L and V550E in the FGFR4 kinase domain have been demonstrated to confer clinical resistance to erdafitinib in rhabdomyosarcoma, while V550M is associated with erdafitinib resistance in breast cancer.

Disease Class: Intrahepatic cholangiocarcinoma [1]

• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Resistant Drug: Erdafitinib
• Molecule Alteration: Missense mutation; p.V550L
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: The mutations V550L and V550E in the FGFR4 kinase domain have been demonstrated to confer clinical resistance to erdafitinib in rhabdomyosarcoma, while V550M is associated with erdafitinib resistance in breast cancer.

Disease Class: Intrahepatic cholangiocarcinoma [1]

• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Resistant Drug: Erdafitinib
• Molecule Alteration: Missense mutation; p.V550E
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: The mutations V550L and V550E in the FGFR4 kinase domain have been demonstrated to confer clinical resistance to erdafitinib in rhabdomyosarcoma, while V550M is associated with erdafitinib resistance in breast cancer.

Disease Class: Breast cancer [1]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Erdafitinib
• Molecule Alteration: Missense mutation; p.V550M
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: The mutations V550L and V550E in the FGFR4 kinase domain have been demonstrated to confer clinical resistance to erdafitinib in rhabdomyosarcoma, while V550M is associated with erdafitinib resistance in breast cancer.

Disease Class: Intrahepatic cholangiocarcinoma [1]

• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Resistant Drug: Erdafitinib
• Molecule Alteration: Missense mutation; p.V550L
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: The mutations V550L and V550E in the FGFR4 kinase domain have been demonstrated to confer clinical resistance to erdafitinib in rhabdomyosarcoma, while V550M is associated with erdafitinib resistance in breast cancer.

Disease Class: Intrahepatic cholangiocarcinoma [1]

• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.1]
• Resistant Drug: Erdafitinib
• Molecule Alteration: Missense mutation; p.V550E
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: The mutations V550L and V550E in the FGFR4 kinase domain have been demonstrated to confer clinical resistance to erdafitinib in rhabdomyosarcoma, while V550M is associated with erdafitinib resistance in breast cancer.

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

PD173074

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Alveolar rhabdomyosarcoma [2]

• Sensitive Disease: Alveolar rhabdomyosarcoma [ICD-11: 2B55.0]
• Sensitive Drug: PD173074
• Molecule Alteration: Missense mutation; p.N535K (c.1605C>G)
• Experimental Note: Identified from the Human Clinical Data

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

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: 2.06E-04; Fold-change: 1.90E-01; Z-score: 5.56E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.25E-24; Fold-change: 5.62E-01; Z-score: 1.30E+00
• The Expression Level of Disease Section Compare with the Other Disease Section: p-value: 3.24E-01; Fold-change: 1.36E-01; Z-score: 3.88E-01

Breast cancer [ICD-11: 2C60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Breast tissue
• The Specified Disease: Breast cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.61E-47; Fold-change: 2.84E-01; Z-score: 1.01E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 3.27E-06; Fold-change: 3.97E-01; Z-score: 8.41E-01

References

• Ref 1: 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 2: Targeting wild-type and mutationally activated FGFR4 in rhabdomyosarcoma with the inhibitor ponatinib (AP24534)PLoS One. 2013 Oct 4;8(10):e76551. doi: 10.1371/journal.pone.0076551. eCollection 2013.