X-Linked Inhibitor of Apoptosis Protein Inhibits Apoptosis in Inflammatory Breast Cancer Cells with Acquired Resistance to an ErbB1/2 Tyrosine Kinase Inhibitor

摘要

Inflammatory breast cancer (IBC) is a highly aggressive subtype of breast cancer that is often characterized by ErbB2 overexpression. ErbB2 targeting is clinically relevant using trastuzumab (anti-ErbB2 antibody) and lapatinib (small molecule ErbB1/2 inhibitor). However, acquired resistance is a common outcome even in IBC patients who show an initial clinical response, which limits the efficacy of these agents. In the present study, using a clonal population of (lapatinib analog, ErbB1/2 inhibitor)-resistant IBC cells, we identified overexpression of an anti-apoptotic protein, XIAP, in acquired resistance to in both ErbB2 overexpressing SUM190 and ErbB1 activated SUM149 cell lines derived from primary IBC tumors. A marked decrease in p-ErbB2, p-ErbB1, and downstream signaling was evident in the -resistant cells (rSUM190 and rSUM149) similar to parental counterparts treated with the drug, suggesting the primary mechanism of action of was not compromised in resistant cells. However, rSUM190 and rSUM149 cells growing in had significant XIAP overexpression and resistance to -mediated apoptosis. Additionally, stable XIAP overexpression using a lentiviral system reversed sensitivity to in parental cells. The observed overexpression was identified to be caused by IRES-mediated XIAP translation. XIAP downregulation in rSUM190 and rSUM149 cells using a small molecule inhibitor (embelin), which abrogates the XIAP/procaspase 9 interaction, resulted in decreased viability, demonstrating that XIAP is required for survival of cells with acquired resistance to . These studies establish the feasibility of development of an XIAP inhibitor that potentiates apoptosis for use in IBC patients with resistance to ErbB2-targeting agents.