Type

Journal Article

Authors

Lorraine O'Driscoll
Annette T Byrne
Martina Gogarty
John Crown
Norma O'Donovan
Brigid C Browne
Martina S McDermott
Stephen Madden
Susan Breslin
Serena Germano
and 3 others

Subjects

Microbiology

Topics
antineoplastic agents humans metabolism tumor burden protein kinase inhibitors female gene knockdown techniques genetics neuropeptides drug therapy cell line tumor inhibitors biological transport cell movement pathology mortality xenograft model antitumor assays resistance pharmacology animals phenotype prognosis neoplasm metastasis therapeutic drug resistance neoplasm tumor markers biological disease models animal antagonists inhibitors breast neoplasms receptor erbb 2 neuromedin u tyrosine kinase biomarker rna messenger

Neuromedin U: a candidate biomarker and therapeutic target to predict and overcome resistance to HER-tyrosine kinase inhibitors. (2014)

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.
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Full list of authors on original publication

Lorraine O'Driscoll, Annette T Byrne, Martina Gogarty, John Crown, Norma O'Donovan, Brigid C Browne, Martina S McDermott, Stephen Madden, Susan Breslin, Serena Germano and 3 others

Experts in our system

1
Lorraine O'Driscoll
Trinity College Dublin
Total Publications: 164
 
2
Annette T Byrne
Royal College of Surgeons in Ireland
Total Publications: 41
 
3
John Crown
Dublin City University
Total Publications: 104
 
4
Norma O'Donovan
Dublin City University
Total Publications: 59
 
5
Brigid C Browne
Dublin City University
Total Publications: 11
 
6
Martina S J McDermott
Dublin City University
Total Publications: 9
 
7
Stephen F Madden
Dublin City University
Total Publications: 45
 
8
Susan Breslin
Trinity College Dublin
Total Publications: 8