Type

Journal Article

Authors

Norma O'Donovan
John Crown
Neil A O'Brien
Stephen F Madden
Brigid C Browne
Laura Ivers
Alexandra Canonici
Martina S J McDermott

Subjects

Biochemistry

Topics
her2 positive cancer cells disease free survival cell cycle arrest breast cancer cancer cell lines response inhibition gene expression

Dual inhibition of IGF1R and ER enhances response to trastuzumab in HER2 positive breast cancer cells. (2017)

Abstract Although HER2 targeted therapies have improved prognosis for HER2 positive breast cancer, HER2 positive cancers which co-express ER have poorer response rates to standard HER2 targeted therapies, combined with chemotherapy, than HER2 positive/ER negative breast cancer. Administration of hormone therapy concurrently with chemotherapy and HER2 targeted therapy is generally not recommended. Using publically available gene expression datasets we found that high expression of IGF1R is associated with shorter disease-free survival in patients whose tumors are ER positive and HER2 positive. IGF1R is frequently expressed in HER2 positive breast cancer and there is significant evidence for crosstalk between IGF1R and both HER2 and ER. Therefore, we evaluated the therapeutic potential of targeting ER and IGF1R in cell line models of HER2/ER/IGF1R positive breast cancer, using tamoxifen and two IGF1R targeted tyrosine kinase inhibitors (NVP-AEW541 and BMS-536924). Dual inhibition of ER and IGF1R enhanced growth inhibition in the four HER2 positive cell lines tested and caused an increase in cell cycle arrest in G1 in BT474 cells. In addition, combined treatment with trastuzumab, tamoxifen and either of the IGF1R TKIs enhanced response compared to dual targeting strategies in three of the four HER2 positive breast cancer cell lines tested. Furthermore, in a cell line model of trastuzumab-resistant HER2 positive breast cancer (BT474/Tr), tamoxifen combined with an IGF1R TKI produced a similar enhanced response as observed in the parental BT474 cells suggesting that this combination may overcome acquired trastuzumab resistance in this model. Combining ER and IGF1R targeting with HER2 targeted therapies may be an alternative to HER2 targeted therapy and chemotherapy for patients with HER2/ER/IGF1R positive breast cancer.
Collections Ireland -> Dublin City University -> PubMed

Full list of authors on original publication

Norma O'Donovan, John Crown, Neil A O'Brien, Stephen F Madden, Brigid C Browne, Laura Ivers, Alexandra Canonici, Martina S J McDermott

Experts in our system

1
Norma O'Donovan
Dublin City University
Total Publications: 59
 
2
John Crown
Dublin City University
Total Publications: 104
 
3
Neil A O'Brien
Dublin City University
Total Publications: 9
 
4
Stephen F Madden
Dublin City University
Total Publications: 45
 
5
Brigid C Browne
Dublin City University
Total Publications: 11
 
6
Alexandra Canonici
Dublin City University
 
7
Martina S J McDermott
Dublin City University
Total Publications: 9