Roles of BIM induction and survivin downregulation in lapatinib-induced apoptosis in breast cancer cells with HER2 amplification

摘要: Lapatinib, a dual tyrosine kinase inhibitor of the epidermal growth factor receptor and human 2 (HER2), is clinically active in patients with breast cancer positive for HER2 amplification. The mechanism this anti-tumor action has remained unclear, however. We have now investigated effects lapatinib amplification-positive cells or without an activating PIK3CA mutation. Lapatinib induced apoptosis association upregulation pro-apoptotic protein Bcl-2 interacting mediator cell death (BIM) through inhibition MEK-ERK signaling pathway RNA interference (RNAi)-mediated depletion BIM inhibited lapatinib-induced apoptosis, implicating induction process. effect was less pronounced mutation than those one. failed to inhibit AKT phosphorylation mutant cells, likely because hyperactivation phosphatidylinositol 3-kinase (PI3K) by Depletion (a catalytic subunit PI3K) revealed that survivin expression regulated PI3K these suggesting insufficient PI3K-survivin responsible limited Consistent notion, RNAi treatment markedly increased level treated lapatinib. Our results thus suggest both MEK-ERK-BIM pathways required effective