Abstract

~20% of breast cancers are HER2+. While HER2 therapies exist, patient response is heterogeneous. Stromal Fibroblasts, an abundant cell type in the breast tumor microenvironment, have been linked to poor patient prognosis. A recent study has demonstrated fibroblast co-culture significantly reduces the efficacy of Lapatinib, a HER2 targeted therapy, in a subset of HER2+ breast cancers cell lines in vitro. To gain a mechanistic understanding of Fibroblast-mediated Lapatinib resistance, a mathematical model is developed. The model relates the PI3K/Akt pathway signaling cascade and protective stromal fibroblast signaling to overall cell growth. Model fit for temporal PI3K/Akt pathway protein expression was informed from Reverse Phase Protein Array data. Model fit for overall cell growth was informed from cellular viability data. Monoculture and Co-culture model variants were generated to represent both a HER2+ fibroblast-protected cell line (BT 474), and a HER2+ fibroblast-insensitive cell line (HCC 1954), under 0.1 μM Lapatinib assault. Parameter sensitivity analysis revealed fibroblast co-culture dramatically increased BT 474 cell sensitivity to pro-growth PI3K/Akt pathway signaling mechanisms, whereas fibroblast co-culture did not affect HCC 1954 cell sensitivity to pro-growth PI3K/Akt pathway signaling mechanisms. Mirroring previously published results, model predictions revealed a combination of Lapatinib and a pAkt inhibitor is the most effective means to arrest cell growth in HCC 1954 as the two drugs act synergistically. Model predictions further revealed a triple-drug combination of Lapatinib, a pAkt inhibitor, and a fibroblast signaling inhibitor is the most effective means to arrest cell growth in BT 474.