Role of XIAP in Therapeutic Resistance in Inflammatory Breast Cancer

摘要

Inflammatory breast cancer (IBC) is a highly aggressive form of locally advanced breast cancer that is often characterized by ErbB2 and ErbB1 overexpression. ErbB-targeting is clinically relevant using trastuzumab, an anti-ErbB2 antibody, and lapatinib, a small molecule ErbB1/2 kinase inhibitor. However, acquired resistance is common even in those patients who show an initial clinical response; this resistance is in part due to apoptotic dysregulation, which allows transformed cells to survive and proliferate, even in the presence of therapeutics. In part, this failure is due to defects in caspase activity, the execution phase of apoptosis. X-linked inhibitor of apoptosis protein (XIAP) is a potent anti-apoptotic protein that is capable of inhibiting both the mitochondrial and extrinsic apoptotic pathways by binding caspases, which inhibits their activation. In studies conducted to date, we have generated both ErbB2 overexpressing SUM190 and ErbB1 activated SUM149 IBC cells with stable XIAP overexpression and shown that this can reverse sensitivity of these cells to GW583340, a lapatinib analog. Additionally, we have generated GW583340 resistant IBC lines (rSUM190 and rSUM149) and characterized expression of prosurvival and anti-apoptotic proteins in these cells. We have identified overexpression of XIAP in acquired resistance to GW583340 in both SUM190 and SUM149 IBC cell lines.