Treatment of Breast Cancer Cells by IGF1R Tyrosine Kinase Inhibitor Combined with Conventional Systemic Drugs

Aim: Insulin-like growth factor-1 receptor (IGF1R) is a tyrosine kinase receptor mediating cell growth and survival of cancer cells. We studied responses to IGF1R tyrosine kinase inhibitor NVP-AEW541 combined with conventional systemic drugs in breast cancer cell lines of different clinical subtype. Materials and Methods: Sensitivity to NVP-AEW541, single treatment and combinations with tamoxifen, trastuzumab, doxorubicin or paclitaxel, was tested in MCF7, SKBR3 and T47D cells. Cells were assayed for proliferation, cell death, cell cycle distribution and phosphorylation of proteins downstream of IGF1R. Results: Treatment of NVP-AEW541 resulted in reduced proliferation, G-1 cell cycle arrest and reduced phosphorylation of protein kinase B (AKT) and extracellular-signal-regulated protein kinase (ERK). Sensitivity to IGF1R tyrosine kinase inhibition was low in T47D cells, despite their high IGF1R expression. NVP-AEW541 combined with trastuzumab had synergistic cytotoxic effects in T47D cells, and additive effects were shown in MCF7 and SKBR3 cells. Also, combination with doxorubicin had antagonistic effects in T47D cells. Doxorubicin caused up-regulation of phosphoryloted ERK in T47D cells, which was not inhibited by NVP-AEW541. Conclusion: Antagonistic effects should be anticipated when IGF1R inhibitors are combined with conventional systemic drugs in a subset of breast tumors. Development of functional biomarkers predicting tumor response to tailored IGF1R therapy is warranted