Molecule Information

General Information of the Molecule (ID: Mol00370)

• Name: Fibroblast growth factor 2 (FGF1) ,Homo sapiens
• Synonyms: FGF-2; Basic fibroblast growth factor; bFGF; Heparin-binding growth factor 2; HBGF-2; FGFB
• Molecule Type: Protein
• Gene Name: FGF2
• Gene ID: 2247
• Location: chr4:122826708-122898236[+]
• Sequence:
  MVGVGGGDVEDVTPRPGGCQISGRGARGCNGIPGAAAWEAALPRRRPRRHPSVNPRSRAA
  GSPRTRGRRTEERPSGSRLGDRGRGRALPGGRLGGRGRGRAPERVGGRGRGRGTAAPRAA
  PAARGSRPGPAGTMAAGSITTLPALPEDGGSGAFPPGHFKDPKRLYCKNGGFFLRIHPDG
  RVDGVREKSDPHIKLQLQAEERGVVSIKGVCANRYLAMKEDGRLLASKCVTDECFFFERL
  ESNNYNTYRSRKYTSWYVALKRTGQYKLGSKTGPGQKAILFLPMSAKS
• 3D-structure: PDB ID: 8OM6; Classification: Cytokine; Method: X-ray diffraction; Resolution: 1.31 Å
• Function: Acts as a ligand for FGFR1, FGFR2, FGFR3 and FGFR4. Also acts as an integrin ligand which is required for FGF2 signaling. Binds to integrin ITGAV:ITGB3. Plays an important role in the regulation of cell survival, cell division, cell differentiation and cell migration. Functions as a potent mitogen in vitro. Can induce angiogenesis. Mediates phosphorylation of ERK1/2 and thereby promotes retinal lens fiber differentiation.
• Uniprot ID: FGF2_HUMAN
• Ensembl ID: ENSG00000138685
• HGNC ID: HGNC:3676

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) 8 drug(s) in total

Erlotinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Pancreatic cancer [ICD-11: 2C10.3] [1]

• Sensitive Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Sensitive Drug: Erlotinib
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Pancreatic cancer [ICD-11: 2C10]
• The Specified Disease: Pancreatic cancer
• The Studied Tissue: Pancreas
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.42E-01; Fold-change: -4.67E-02; Z-score: -9.76E-01
• 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.

Cyclophosphamide

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [ICD-11: 2C60.3] [2]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Sensitive Drug: Cyclophosphamide
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Breast cancer [ICD-11: 2C60]
• The Specified Disease: Breast cancer
• The Studied Tissue: Breast tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.31E-121; Fold-change: -4.76E-01; Z-score: -3.54E+01
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Regulation; N.A.
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Drug resistance clonogenic assay
• Mechanism Description: miR-205 enhances chemosensitivity of breast cancer cells to TAC chemotherapy by suppressing both VEGFA and FGF2, leading to evasion of apoptosis.

Carboplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Ovarian cancer [ICD-11: 2C73.0] [3]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Carboplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780DPP cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: SKOV-3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: Caov-3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• Experiment for Molecule Alteration: qRT-PCR; Immunoblotting assay
• Experiment for Drug Resistance: MTT assay; In vitro chemosensitivity assay
• Mechanism Description: Pharmacological inhibition of FGF signalling reversed drug resistance in immortalised cell lines and in primary cell lines from drug-resistant ovarian cancer patients, while FGF1 over-expression induced resistance.FGF receptor inhibition re-sensitises cells to cisplatin and carboplatin. Ataxia telangiectasia mutated (ATM) phosphorylation, but not DNA adduct formation was FGF1 dependent, following cisplatin or carboplatin challenge. Combining platinum drugs with the ATM inhibitor KU55933, but not with the DNA-PK inhibitor NU7027 re-sensitised resistant cells.

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Ovarian cancer [ICD-11: 2C73.0] [3]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780DPP cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: SKOV-3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: Caov-3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• Experiment for Molecule Alteration: qRT-PCR; Immunoblotting assay
• Experiment for Drug Resistance: MTT assay; In vitro chemosensitivity assay
• Mechanism Description: Pharmacological inhibition of FGF signalling reversed drug resistance in immortalised cell lines and in primary cell lines from drug-resistant ovarian cancer patients, while FGF1 over-expression induced resistance.FGF receptor inhibition re-sensitises cells to cisplatin and carboplatin. Ataxia telangiectasia mutated (ATM) phosphorylation, but not DNA adduct formation was FGF1 dependent, following cisplatin or carboplatin challenge. Combining platinum drugs with the ATM inhibitor KU55933, but not with the DNA-PK inhibitor NU7026 re-sensitised resistant cells.

Docetaxel

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [ICD-11: 2C60.3] [2]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Sensitive Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Regulation; N.A.
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Drug resistance clonogenic assay
• Mechanism Description: miR-205 enhances chemosensitivity of breast cancer cells to TAC chemotherapy by suppressing both VEGFA and FGF2, leading to evasion of apoptosis.

Doxorubicin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [ICD-11: 2C60.3] [2]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Regulation; N.A.
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Drug resistance clonogenic assay
• Mechanism Description: miR-205 enhances chemosensitivity of breast cancer cells to TAC chemotherapy by suppressing both VEGFA and FGF2, leading to evasion of apoptosis.

Gemcitabine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Pancreatic cancer [ICD-11: 2C10.3] [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.

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] [4]

• Resistant Disease: Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
• Resistant Drug: Imatinib
• Molecule Alteration: Expression; 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).

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: 3.42E-01; Fold-change: -4.17E-02; Z-score: -5.84E-02
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 6.78E-03; Fold-change: 3.32E-01; Z-score: 4.97E-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: 1.31E-121; Fold-change: -2.30E+00; Z-score: -2.70E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 2.49E-15; Fold-change: -1.92E+00; Z-score: -1.79E+00

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: miRNA-205 targets VEGFA and FGF2 and regulates resistance to chemotherapeutics in breast cancer. Cell Death Dis. 2016 Jun 30;7(6):e2291. doi: 10.1038/cddis.2016.194.
• Ref 3: Fibroblast growth factor signalling influences homologous recombination-mediated DNA damage repair to promote drug resistance in ovarian cancer. Br J Cancer. 2022 Oct;127(7):1340-1351.
• Ref 4: 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.