Abstract 951: Cross-resistance and re-sensitization to multiple drugs in an IBC model of lapatinib acquired resistance parallels redox adaptation

Inflammatory breast cancer (IBC) is characterized by rapid progression from onset of disease, therefore an early and aggressive multimodal therapy is essential to improve outcome. IBC tumors are frequently ErbB2- and EGFR-positive, and the use of trastuzumab in combination with lapatinib has seen clinical success; however, de novo and acquired resistance to these agents due to interplay between different members of the ErbB family is a significant challenge. In addition, it is well recognized that there is paucity of IBC cellular models. We have characterized a novel isogenic-derived progression model of lapatinib drug resistance (rSUM149) and re-sensitization (rrSUM149). Four IBC cell lines representing either HER2 overexpression or basal-type were profiled to identify approved oncology drugs from that can act as potent inhibitors of IBC cell proliferation. In our present study, rSUM149 cells showed cross-resistance to a number of the drugs previously shown to act on the parental cells. We show that long term removal of lapatinib, the primary drug against which resistance was developed from rSUM149 cells led to isolation of a population of cells (rrSUM149) that are then re-sensitized to multiple drugs, behaving in a manner comparable to the parental SUM149 cell line. Recently, we identified that the lapatinib-resistant rSUM149 had increased levels of anti-apoptotic proteins, increased antioxidant expression (superoxide dismutase and GSH), and decreased ability to accumulate reactive oxygen species (ROS), all of which lead to inhibition of drug-induced apoptosis. We had previously validated this finding with the observations that: (i). Overexpressing XIAP in therapy-sensitive IBC cells renders them therapy-resistant and this corresponds to low ROS accumulation in response to oxidative stress; (ii). specific XIAP inhibition using siRNA or XIAP small molecule inhibitors reversed drug resistance, decreased the antioxidants involved in redox-adaptation and increased significant ROS accumulation leading to IBC cell death. In our results presented herein, re-sensitization was accompanied by a decrease in expression of the apoptosis inhibitor XIAP and antioxidant SOD2; assessment of ROS following challenge with lapatinib revealed that the ability to accumulate ROS was restored to the cells through those changes. This mechanistic phenotype supports our current observations of cross-resistance to multiple drugs, which is also commonly seen in patients. These result