Background: LCL161, a SMAC’S small molecule mimetic, can bind to a variety of IAPs and activate
Caspases. We found that on its own, LCL161induces apoptosis of drug-resistant breast cancer cells by
binding to a variety of IAPs and activating Caspases. However, when LCL161 is used in combination with
Caspase Inhibitors (CI), its capacity to induce apoptosis of breast cancer cells is enhanced.
Objective: To carry out proteomic and bioinformatics analysis of LCL161 in combination with CI. We aim to
identify the key proteins and mechanisms of breast cancer drug-resistant apoptosis, thereby aiding in the breast
cancer drug resistance treatment and identification of drug targeting markers.
Methods: Cell culture experiments were carried out to explore the effect of LCL161 combined with CI on the
proliferation of breast cancer drug-resistant cells. Proteomic analysis was carried out to determine the protein
expression differences between breast cancer drug-resistant cells and LCL161 combined with CI treated cells.
Bioinformatics analysis was carried out to determine its mechanism of action. Validation of proteomics results
was done using Parallel Reaction Monitoring (PRM).
Results: Cell culture experiments showed that LCL161 in combination with CI can significantly promote the
apoptosis of breast cancer drug-resistant cells. Up-regulation of 92 proteins and down-regulation of 114 proteins
protein were noted, of which 4 were selected for further validation.
Conclusion: Our results show that LCL161 combined with CI can promote the apoptosis of drug-resistant breast
cancer cells by down-regulation of RRM2, CDK4, and ITGB1 expression through Cancer pathways, p53 or
PI3K-AKT signaling pathway. In addition, the expression of CDK4, RRM2, and CDC20 can be down-regulated
by the nuclear receptor pathway to affect DNA transcription and replication, thereby promoting apoptosis of
breast cancer drug-resistant cells.