Inhibition of IGF1R activity enhances response to trastuzumab in HER-2-positive breast cancer cells

• Published in: Annals of oncology Vol. 22; no. 1; pp. 68 - 73
• Main Authors: Browne, B.C., Crown, J., Venkatesan, N., Duffy, M.J., Clynes, M., Slamon, D., O'Donovan, N.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-01-2011; Oxford University Press
• Subjects: Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - enzymology; Breast Neoplasms - genetics; Breast Neoplasms - therapy; Cell Growth Processes - drug effects; Cell Line, Tumor; Combined Modality Therapy; Drug Resistance, Neoplasm; Drug Synergism; Female; Gynecology. Andrology. Obstetrics; HER-2; Herceptin; Humans; IGF1R; Mammary gland diseases; Medical sciences; NVP-AEW541; Pharmacology. Drug treatments; Protein Kinase Inhibitors - administration & dosage; Pyrimidines - administration & dosage; Pyrroles - administration & dosage; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - biosynthesis; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Receptor, IGF Type 1 - antagonists & inhibitors; Receptor, IGF Type 1 - genetics; Receptor, IGF Type 1 - metabolism; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - genetics; Transfection; Trastuzumab; Tumors; Herceptin; trastuzumab; breast cancer; HER-2; NVP-AEW541; IGF1R; Antineoplastic agent; Breast disease; erbB2 Gene; Breast cancer; Malignant tumor; Monoclonal antibody; Biological activity; Human Epidermal growth factor Receptor 2; type I insulin-like growth factor receptor; Mammary gland diseases; C-Onc gene; Inhibitor; Inhibition; Tumor cell; Protooncogene; Trastuzumab; Cancer
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1093/annonc/mdq349

Background: Although trastuzumab has improved the prognosis for HER-2-positive breast cancer patients, not all HER-2-positive breast tumours respond to trastuzumab treatment and those that initially respond frequently develop resistance. Insulin-like growth factor-1 receptor (IGF1R) signalling has been previously implicated in trastuzumab resistance. We tested IGF1R inhibition to determine if dual targeting of HER-2 and IGF1R improves response in cell line models of acquired trastuzumab resistance.
Materials and methods: HER-2, IGF1R, phospho-HER-2, and phospho-IGF1R levels were measured by enzyme-linked immunosorbent assays in parental and trastuzumab-resistant SKBR3 and BT474 cells. IGF1R signalling was targeted in these cells using both small interfering RNA (siRNA) and the tyrosine kinase inhibitor, NVP-AEW541.
Results: IGF1R levels were significantly increased in the trastuzumab-resistant model, SKBR3/Tr, compared with the parental SKBR3 cell line. In both the SKBR3/Tr and BT474/Tr cell lines, inhibition of IGF1R expression with siRNA or inhibition of tyrosine kinase activity by NVP-AEW541 significantly increased response to trastuzumab. The dual targeting approach also improved response in the parental SKBR3 cells but not in the BT474 parental cells.
Conclusions: Our results confirm that IGF1R inhibition improves response to trastuzumab in HER-2-positive breast cancer cells and suggest that dual targeting of IGF1R and HER-2 may improve response in HER-2-positive tumours.