High IGF-IR Activity in Triple-Negative Breast Cancer Cell Lines Correlates with Sensitivity to IGF-IR Inhibitor BMS-754807 in This Subtype of Human Breast Cancer.

Abstract

Abstract BACKGROUND: Evidence implicates insulin-like growth factor-I (IGF-I) signaling in the development and progression of breast cancer. Within the last few years several drugs targeting IGF-I receptor (IGF-IR) have entered clinical trials and are showing promising early results. BMS-754807 is a new small molecule inhibitor of IGF-IR in Phase 1 clinical trials.METHODS: Minimal and maximal IC50 to BMS-754807 for monolayer proliferation was determined for a panel of 30 breast cancer cell lines. Comparative gene expression analysis was performed using publicly available gene expression among the most resistant and sensitive cell lines. Q-RT-PCR was used to validate gene expression differences. Using the IGF gene signature, we scored each expression profile in a panel of cell lines and tumorgrafts, for correlation with the IGF-induced patterns. IGF-IR and pY-IGF-IR levels were determined in human tumorgrafts by immunohistochemistry.RESULTS: Among the different tumor cell lines, sensitivity to BMS-754807 varied widely from 0.1µM to 25µM. When defining cell lines as sensitive or resistant based on the median IC50, there was a strong enrichment for triple negative (TN; ERa-/PR-/HER2-) breast cancer cell lines in the sensitive group (11/15), while luminal breast cancer cell lines were generally resistant (11/15). We identified 136 differentially expressed genes between sensitive and resistance cell lines. Sensitive breast cancer cell lines preferentially express genes such as CAV1, and CAV2 while resistant cell lines were associated with high expression of ErbB3, and SPDEF. As luminal breast cancer cell lines were generally resistant to BMS-754807, we examined the role of estrogen and ERa on the sensitivity to BMS-754807. ERa mRNA levels strongly correlated with resistance to BMS-754807. Consistent with this, estrogen-withdrawal sensitized luminal breast cancer cells to BMS-754807. Previously, we developed an IGF-I gene signature that was derived from breast cancer cells stimulated with IGF-I, and reported that the signature strongly correlated with the TN subtype of human breast cancer. Consistent with this observation, we found that the IGF-I signature was high in TN breast cancer cell lines, and the IGF-I signature correlated with sensitivity to BMS-754807. To examine this further, we measured IGF-IR and pY-IGF-IR levels in four recently developed tumorgraft models of TN human breast cancer and found strong reactivity in half of the models. Interestingly, the tumorgraft (MC1) with the highest IGF-IR levels and activity showed the strongest enrichment for the IGF-I gene signature.CONCLUSIONS: In summary, our data indicates that the IGF-I pathway is highly active in TN breast cancer and this study provides the preclinical rationale for targeting IGF-IR in this subtype of human breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1132.