title: Neuromedin U: a candidate biomarker and therapeutic target to predict and overcome resistance to HER-tyrosine kinase inhibitors.
abstract: Intrinsic and acquired resistance to HER-targeting drugs occurs in a significant proportion of HER2-overexpressing breast cancers. Thus, there remains a need to identify predictive biomarkers that could improve patient selection and circumvent these types of drug resistance. Here, we report the identification of neuromedin U (NmU) as an extracellular biomarker in cells resistant to HER-targeted drugs. NmU overexpression occurred in cells with acquired or innate resistance to lapatinib, trastuzumab, neratinib, and afatinib, all of which displayed a similar trend upon short-term exposure, suggesting NmU induction may be an early response. An analysis of 3,489 cases of breast cancer showed NmU to be associated with poor patient outcome, particularly those with HER2-overexpressing tumors independent of established prognostic indicators. Ectopic overexpression of NmU in drug-sensitive cells conferred resistance to all HER-targeting drugs, whereas RNAi-mediated attenuation sensitized cells exhibiting acquired or innate drug resistance. Mechanistic investigations suggested that NmU acted through HSP27 as partner protein to stabilize HER2 protein levels. We also obtained evidence of functional NmU receptors on HER2-overexpressing cells, with the addition of exogenous NmU eliciting an elevation in HER2 and EGFR expression along with drug resistance. Finally, we found that NmU seemed to function in cell motility, invasion, and anoikis resistance. In vivo studies revealed that NmU attenuation impaired tumor growth and metastasis. Taken together, our results defined NmU as a candidate drug response biomarker for HER2-overexpressing cancers and as a candidate therapeutic target to limit metastatic progression and improve the efficacy of HER-targeted drugs.
authors.affiliation: Authors' Affiliations: School of Pharmacy and Pharmaceutical Sciences & Trinity Biomedical Sciences Institute, Trinity College Dublin;
authors.forename: Sweta
authors.initials: S
authors.lastname: Rani
authors.affiliation: Authors' Affiliations: School of Pharmacy and Pharmaceutical Sciences & Trinity Biomedical Sciences Institute, Trinity College Dublin;
authors.forename: Claire
authors.initials: C
authors.lastname: Corcoran
authors.affiliation: Department of Physiology & Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland;
authors.forename: Liam
authors.initials: L
authors.lastname: Shiels
authors.affiliation: Authors' Affiliations: School of Pharmacy and Pharmaceutical Sciences & Trinity Biomedical Sciences Institute, Trinity College Dublin;
authors.forename: Serena
authors.initials: S
authors.lastname: Germano
authors.affiliation: Authors' Affiliations: School of Pharmacy and Pharmaceutical Sciences & Trinity Biomedical Sciences Institute, Trinity College Dublin;
authors.forename: Susan
authors.initials: S
authors.lastname: Breslin
authors.affiliation: Molecular Therapeutics for Cancer Ireland, Dublin City University;
authors.forename: Stephen
authors.initials: S
authors.lastname: Madden
authors.affiliation: Molecular Therapeutics for Cancer Ireland, Dublin City University;
authors.forename: Martina S
authors.initials: MS
authors.lastname: McDermott
authors.affiliation: Molecular Therapeutics for Cancer Ireland, Dublin City University;
authors.forename: Brigid C
authors.initials: BC
authors.lastname: Browne
authors.affiliation: Molecular Therapeutics for Cancer Ireland, Dublin City University;
authors.forename: Norma
authors.initials: N
authors.lastname: O'Donovan
authors.affiliation: Department of Oncology, St. Vincent's University Hospital; and.
authors.forename: John
authors.initials: J
authors.lastname: Crown
authors.affiliation: Authors' Affiliations: School of Pharmacy and Pharmaceutical Sciences & Trinity Biomedical Sciences Institute, Trinity College Dublin;
authors.forename: Martina
authors.initials: M
authors.lastname: Gogarty
authors.affiliation: Department of Physiology & Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland; School of Biomolecular & Biomedical Science, University College Dublin, Conway Institute, Dublin, Ireland.
authors.forename: Annette T
authors.initials: AT
authors.lastname: Byrne
authors.affiliation: Authors' Affiliations: School of Pharmacy and Pharmaceutical Sciences & Trinity Biomedical Sciences Institute, Trinity College Dublin; lodrisc@tcd.ie.
authors.forename: Lorraine
authors.initials: L
authors.lastname: O'Driscoll
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001692:Biological Transport; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D009362:Neoplasm Metastasis; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D009479:Neuropeptides; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; C056900:neuromedin U