Quantitative high-throughput efficacy profiling of approved oncology drugs in inflammatory breast cancer models of acquired drug resistance and re-sensitization

• A qHTS format was used to profile FDA approved oncology drugs for effects on cell proliferation in IBC models.
• IBC cell lines included matched isogenic models of acquired resistance to lapatinib and resistance reversal.
• Lapatinib-resistant cells with increased anti-apoptotic proteins and redox adaptation were cross-resistant to multiple drugs.
• Reversal of lapatinib resistance cells had increased ROS-generating capabilities and regained sensitivity to multiple drugs.
• Modulation of cellular redox is an attractive strategy to prevent and overcome drug resistance in IBC.

Although there is no standard treatment protocol for inflammatory breast cancer (IBC), multi-modality treatment has improved survival. In this study we profiled the NCI approved oncology drug set in a qHTS format to identify those that are efficacious in basal type and ErbB2 overexpressing IBC models. Further, we characterized the sensitivity of an acquired therapeutic resistance model to the oncology drugs. We observed that lapatinib-induced acquired resistance in SUM149 cells led to cross-resistance to other targeted- and chemotherapeutic drugs. Removal of the primary drug to which the model was developed led to re-sensitization to multiple drugs to a degree comparable to the parental cell line; this coincided with the cells regaining the ability to accumulate ROS and reduced expression of anti-apoptotic factors and the antioxidant SOD2. We suggest that our findings provide a unique IBC model system for gaining an understanding of acquired therapeutic resistance and the effect of redox adaptation on anti-cancer drug efficacy.