Molecule Information

General Information of the Molecule (ID: Mol04395)

• Name: Pro-neuregulin-1, membrane-bound isoform (NRG1) ,Homo sapiens
• Molecule Type: Protein
• Gene Name: NRG1
• Gene ID: 3084
• Sequence:
  MSERKEGRGKGKGKKKERGSGKKPESAAGSQSPALPPRLKEMKSQESAAGSKLVLRCETS
  SEYSSLRFKWFKNGNELNRKNKPQNIKIQKKPGKSELRINKASLADSGEYMCKVISKLG
  N DSASANITIVESNEIITGMPASTEGAYVSSESPIRISVSTEGANTSSSTSTSTTGTSH
  LV KCAEKEKTFCVNGGECFMVKDLSNPSRYLCKCQPGFTGARCTENVPMKVQNQEKAEE
  LYQ KRVLTITGICIALLVVGIMCVVAYCKTKKQRKKLHDRLRQSLRSERNNMMNIANGP
  HHPN PPPENVQLVNQYVSKNVISSEHIVEREAETSFSTSHYTSTAHHSTTVTQTPSHSW
  SNGHT ESILSESHSVIVMSSVENSRHSSPTGGPRGRLNGTGGPRECNSFLRHARETPDS
  YRDSPH SERYVSAMTTPARMSPVDFHTPSSPKSPPSEMSPPVSSMTVSMPSMAVSPFME
  EERPLLL VTPPRLREKKFDHHPQQFSSFHHNPAHDSNSLPASPLRIVEDEEYETTQEYE
  PAQEPVKK LANSRRAKRTKPNGHIANRLEVDSNTSSQSSNSESETEDERVGEDTPFLGI
  QNPLAASLE ATPAFRLADSRTNPAGRFSTQEEIQARLSSVIANQDPIAV
• 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. The multiple isoforms perform diverse functions such asinducing growth and differentiation of epithelial, glial, neuronal, andskeletal muscle cells; inducing expression of acetylcholine receptor insynaptic vesicles during the formation of the neuromuscular junction;stimulating lobuloalveolar budding and milk production in the mammarygland and inducing differentiation of mammary tumor cells; stimulatingSchwann cell proliferation; implication in the development of themyocardium such as trabeculation of the developing heart. Isoform 10may play a role in motor and sensory neuron development. Binds to ERBB4. Binds to ERBB3 .Acts as a ligand for integrins and binds to integrinsITGAV:ITGB3 or ITGA6:ITGB4. Its binding to integrins and subsequentternary complex formation with integrins and ERRB3 are essential forNRG1-ERBB signaling. Induces the phosphorylation and activation ofMAPK3/ERK1, MAPK1/ERK2 and AKT1 . Ligand-dependentERBB4 endocytosis is essential for the NRG1-mediated activation ofthese kinases in neurons .{ECO:0000250|UniProtKB:P43322, ECO:0000269|PubMed:10867024,ECO:0000269|PubMed:1348215, ECO:0000269|PubMed:20682778,ECO:0000269|PubMed:7902537}.
• Uniprot ID: NRG1_HUMAN
• Ensembl ID: ENSG0000015716822
• HGNC ID: HGNC:7997

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Alectinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [1]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Alectinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR signaling pathway; Activation; hsa01521
• Cell Pathway Regulation: HER3 signaling pathway; Regulation; N.A.
• In Vitro Model: ALK1903 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: DTP cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay; qRT-PCR
• Experiment for Drug Resistance: CellTiter-Glo 3D cell viability assay
• Mechanism Description: DTP cells evade ALK-TKI-induced cell death through activation of EGFR and HER3 signaling.

Enzalutamide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Prostate cancer [ICD-11: 2C82.0] [2]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Enzalutamide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DU145-EnzR cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: CAFs significantly promoted cell growth and enzalutamide resistance of PC3-EnzR and DU145-EnzR cells through substantial increased secretion of NRG1 by CAFs. Co-culturing enzalutamide-resistant prostate cancer cells (PC3-EnzR and DU145-EnzR) with CAFs further enhanced enzalutamide resistance, as evidenced by elevated IC50 values. Inhibition of NRG1 in CAFs attenuated their impact on enzalutamide resistance, providing insight into the role of NRG1 in mediating the crosstalk between CAFs and prostate cancer in the context of enzalutamide resistance. This study elucidates the pivotal role of CAF-secreted NRG1 in promoting enzalutamide resistance in prostate cancer, providing valuable insights for developing targeted therapeutic strategies to overcome resistance in advanced prostate cancer.

References

• Ref 1: Combined blockade of GPX4 and activated EGFR/HER3 bypass pathways inhibits the development of ALK-inhibitor-induced tolerant persister cells in ALK-fusion-positive lung cancer. Mol Oncol. 2025 Feb;19(2):519-539.
• Ref 2: NRG1 secreted by cancer-associated fibroblasts contributes to enzalutamide resistance in prostate cancer cells. Am J Cancer Res. 2024 Oct 15;14(10):4830-4840.