Molecule Information

General Information of the Molecule (ID: Mol04294)

• Name: Pro-neuregulin-2, membrane-bound isoform (NRG2) ,Homo sapiens
• Molecule Type: Protein
• Gene Name: NRG2
• Gene ID: 9542
• Sequence:
  MRQVCCSALPPPPLEKGRCSSYSDSSSSSSERSSSSSSSSSESGSSSRSSSNNSSISRPA
  APPEPRPQQQPQPRSPAARRAAARSRAAAAGGMRRDPAPGFSMLLFGVSLACYSPSLKS
  V QDQAYKAPVVVEGKVQGLVPAGGSSSNSTREPPASGRVALVKVLDKWPLRSGGLQREQ
  VI SVGSCVPLERNQRYIFFLEPTEQPLVFKTAFAPLDTNGKNLKKEVGKILCTDCATRP
  KLK KMKSQTGQVGEKQSLKCEAAAGNPQPSYRWFKDGKELNRSRDIRIKYGNGRKNSRL
  QFNK VKVEDAGEYVCEAENILGKDTVRGRLYVNSVSTTLSSWSGHARKCNETAKSYCVN
  GGVCY YIEGINQLSCKCPNGFFGQRCLEKLPLRLYMPDPKQKAEELYQKRVLTITGICV
  ALLVVG IVCVVAYCKTKKQRKQMHNHLRQNMCPAHQNRSLANGPSHPRLDPEEIQMADY
  ISKNVPA TDHVIRRETETTFSGSHSCSPSHHCSTATPTSSHRHESHTWSLERSESLTSD
  SQSGIMLS SVGTSKCNSPACVEARARRAAAYNLEERRRATAPPYHDSVDSLRDSPHSER
  YVSALTTPA RLSPVDFHYSLATQVPTFEITSPNSAHAVSLPPAAPISYRLAEQQPLLRH
  PAPPGPGPGP GPGPGPGADMQRSYDSYYYPAAGPGPRRGTCALGGSLGSLPASPFRIPE
  DDEYETTQECA PPPPPRPRARGASRRTSAGPRRWRRSRLNGLAAQRARAARDSLSLSSG
  SGGGSASASDDD ADDADGALAAESTPFLGLRGAHDALRSDSPPLCPAADSRTYYSLDSH
  STRASSRHSRGPP PRAKQDSAPL
• Function: Direct ligand for ERBB3 and ERBB4 tyrosine kinase receptors.Concomitantly recruits ERBB1 and ERBB2 coreceptors, resulting inligand-stimulated tyrosine phosphorylation and activation of the ERBBreceptors. May also promote the heterodimerization with the EGFreceptor.
• Uniprot ID: NRG2_HUMAN
• Ensembl ID: ENSG0000015845821
• HGNC ID: HGNC:7998

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

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] [1]

• 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] [1]

• 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: 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.