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

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

doi:10.3892/ijo.2017.3976

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

Authors:
- Martina S.J. McDermott
- Alexandra Canonici
- Laura Ivers
- Brigid C. Browne
- Stephen F. Madden
- Neil A. O'Brien
- John Crown
- Norma O'Donovan
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Affiliations: National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland, Population Health Sciences Division, Royal College of Surgeons in Ireland, Dublin 2, Ireland, Department of Medicine, Division of Haematology/Oncology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
Published online on: April 26, 2017 https://doi.org/10.3892/ijo.2017.3976
Pages: 2221-2228

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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.

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