Molecule Information

General Information of the Molecule (ID: Mol00403)

• Name: Proheparin-binding EGF-like growth factor (HBEGF) ,Homo sapiens
• Synonyms: HB-EGF; HBEGF; Diphtheria toxin receptor; DT-R; DTR; DTS; HEGFL
• Molecule Type: Protein
• Gene Name: HBEGF
• Gene ID: 1839
• Location: chr5:140332843-140346603[-]
• Sequence:
  MKLLPSVVLKLFLAAVLSALVTGESLERLRRGLAAGTSNPDPPTVSTDQLLPLGGGRDRK
  VRDLQEADLDLLRVTLSSKPQALATPNKEEHGKRKKKGKGLGKKRDPCLRKYKDFCIHGE
  CKYVKELRAPSCICHPGYHGERCHGLSLPVENRLYTYDHTTILAVVAVVLSSVCLLVIVG
  LLMFRYHRRGGYDVENEEKVKLGMTNSH
• 3D-structure: PDB ID: 1XDT; Classification: Complex (toxin/growth factor); Method: X-ray diffraction; Resolution: 2.65 Å
• Function: Growth factor that mediates its effects via EGFR, ERBB2 and ERBB4. Required for normal cardiac valve formation and normal heart function. Promotes smooth muscle cell proliferation. May be involved in macrophage-mediated cellular proliferation. It is mitogenic for fibroblasts, but not endothelial cells. It is able to bind EGF receptor/EGFR with higher affinity than EGF itself and is a far more potent mitogen for smooth muscle cells than EGF. Also acts as a diphtheria toxin receptor.
• Uniprot ID: HBEGF_HUMAN
• Ensembl ID: ENSG00000113070
• HGNC ID: HGNC:3059

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) 1 drug(s) in total

Cetuximab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Head and neck squamous cell carcinoma [ICD-11: 2D42.1] [1]

• Resistant Disease: Head and neck squamous cell carcinoma [ICD-11: 2D42.1]
• Resistant Drug: Cetuximab
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Head and neck cancer [ICD-11: 2D42]
• The Specified Disease: Head and neck cancer
• The Studied Tissue: Head and neck tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.24E-14; Fold-change: 1.52E-01; Z-score: 8.29E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SCC1 cells; Tongue; Homo sapiens (Human); CVCL_A5SA
• In Vitro Model: 1Cc8 cells; Epithelium; Homo sapiens (Human); CVCL_L893
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: HB-EGF can induce EMT, enhance metastasis, and modulate chemotherapy resistance. Increased expression of HB-EGF due to down-regulation of miR-212 is a possible mechanism of cetuximab resistance.

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

BTK inhibitors

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2] [2]

• Resistant Disease: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2]
• Resistant Drug: BTK inhibitors
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K-AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: RAS-ERK signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: NF-kappaB signaling pathway; Activation; hsa04218
• In Vitro Model: Karpas1718 cells; Lymph; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR; Flow cytometry; Protein analyses; Immunofluorescence staining assay; Confocal microscopy assay
• Experiment for Drug Resistance: MTT assay; ELISA assay
• Mechanism Description: A mechanism of secondary resistance to the PI3Kdelta and BTK inhibitors in B cell neoplasms driven by secreted factors.Here, we show that the overexpression of ERBB4 and its ligands represents a modality for B cell neoplastic cells to bypass the anti-tumor activity of BTK and PI3K inhibitors.Cellular and genetic experiments demonstrated the involvement of this axis in blocking the anti-tumor activity of various BTK and PI3K inhibitors, currently used in the clinical setting.Multi-omics analysis underlined that an epigenetic reprogramming affected the expression of the resistance-related factors.Our results indicate that activation of ERBB signaling driven by secreted ligands and upregulation of receptors can sustain resistance to BTK and PI3K inhibitors.The mechanism of resistance appeared driven by extensive methylation changes. Promoter methylation changes largely sustained the resistance via downregulation of miRNAs (miR-29 and let-7).In conclusion, we identified a novel ERBB4-driven mechanism of resistance to BTK and PI3K inhibitors

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

PI3K inhibitors

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2] [2]

• Resistant Disease: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2]
• Resistant Drug: PI3K inhibitors
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K-AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: RAS-ERK signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: NF-kappaB signaling pathway; Activation; hsa04218
• In Vitro Model: Karpas1718 cells; Lymph; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR; Flow cytometry; Protein analyses; Immunofluorescence staining assay; Confocal microscopy assay
• Experiment for Drug Resistance: MTT assay; ELISA assay
• Mechanism Description: A mechanism of secondary resistance to the PI3Kdelta and BTK inhibitors in B cell neoplasms driven by secreted factors.Here, we show that the overexpression of ERBB4 and its ligands represents a modality for B cell neoplastic cells to bypass the anti-tumor activity of BTK and PI3K inhibitors.Cellular and genetic experiments demonstrated the involvement of this axis in blocking the anti-tumor activity of various BTK and PI3K inhibitors, currently used in the clinical setting.Multi-omics analysis underlined that an epigenetic reprogramming affected the expression of the resistance-related factors.Our results indicate that activation of ERBB signaling driven by secreted ligands and upregulation of receptors can sustain resistance to BTK and PI3K inhibitors.The mechanism of resistance appeared driven by extensive methylation changes. Promoter methylation changes largely sustained the resistance via downregulation of miRNAs (miR-29 and let-7).In conclusion, we identified a novel ERBB4-driven mechanism of resistance to BTK and PI3K inhibitors

References

• Ref 1: Regulation of heparin-binding EGF-like growth factor by miR-212 and acquired cetuximab-resistance in head and neck squamous cell carcinoma. PLoS One. 2010 Sep 13;5(9):e12702. doi: 10.1371/journal.pone.0012702.
• Ref 2: ERBB4-Mediated Signaling Is a Mediator of Resistance to PI3K and BTK Inhibitors in B-cell Lymphoid Neoplasms. Mol Cancer Ther. 2024 Mar 4;23(3):368-380.