3D organoid modeling identified that targeting IGF1R signaling may overcome drug resistance in breast cancer

Abstract

AbstractBreast cancer is the most frequently diagnosed cancer and the second largest cause of cancer deaths in women. However, drug resistance and poor response to treatments are common. Thus, there is an unmet need to identify new treatments and effective lab-based drug testing methods. Here we established a novel 3-dimensional organoid method by co-culturing cancer cells with healthy endothelial cells for longer-term testing of new drug combinations that combat drug resistance. As a proof-of-concept we showed that paclitaxel efficacy can be improved by combining it with AKT inhibitors. In addition, we identified a new triple combination of paclitaxel, HER2 inhibitor, and IGF1R inhibitor, which is more effective in increasing cell death and reducing organoid growth. Interestingly, many IGF1R pathway members are upregulated in breast cancer patients, and high expression is associated with poor survival, indicating that IGF1R is an attractive therapeutic target. Overall, using this novel organoid method, we can mimic more accurate culture conditions and identify new targets to be tested in clinical trials. Our approach is applicable to various cancers to improve patients’ outcomes.