Department of Medical Oncology, Kinki University, Ohno-higashi, Osaka-Sayama, Japan.
Oncogene. 2011 Sep 29;30(39):4097-106. doi: 10.1038/onc.2011.111. Epub 2011 Apr 18.
Lapatinib, a dual tyrosine kinase inhibitor of the epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), is clinically active in patients with breast cancer positive for HER2 amplification. The mechanism of this anti-tumor action has remained unclear, however. We have now investigated the effects of lapatinib in HER2 amplification-positive breast cancer cells with or without an activating PIK3CA mutation. Lapatinib induced apoptosis in association with upregulation of the pro-apoptotic protein Bcl-2 interacting mediator of cell death (BIM) through inhibition of the MEK-ERK signaling pathway in breast cancer cells with HER2 amplification. RNA interference (RNAi)-mediated depletion of BIM inhibited lapatinib-induced apoptosis, implicating BIM induction in this process. The pro-apoptotic effect of lapatinib was less pronounced in cells with a PIK3CA mutation than in those without one. Lapatinib failed to inhibit AKT phosphorylation in PIK3CA mutant cells, likely because of hyperactivation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway by the mutation. Depletion of PIK3CA (a catalytic subunit of PI3K) revealed that survivin expression is regulated by the PI3K pathway in these cells, suggesting that insufficient inhibition of PI3K-survivin signaling is responsible for the limited pro-apoptotic effect of lapatinib in HER2 amplification-positive cells with a PIK3CA mutation. Consistent with this notion, depletion of survivin by RNAi or treatment with a PI3K inhibitor markedly increased the level of apoptosis in PIK3CA mutant cells treated with lapatinib. Our results thus suggest that inhibition of both PI3K-survivin and MEK-ERK-BIM pathways is required for effective induction of apoptosis in breast cancer cells with HER2 amplification.
拉帕替尼是一种表皮生长因子受体和人表皮生长因子受体 2（HER2）的双重酪氨酸激酶抑制剂，在 HER2 扩增阳性的乳腺癌患者中具有临床活性。然而，这种抗肿瘤作用的机制仍不清楚。我们现在研究了拉帕替尼在 HER2 扩增阳性乳腺癌细胞中的作用，这些细胞或有或无激活的 PIK3CA 突变。拉帕替尼通过抑制 MEK-ERK 信号通路，诱导乳腺癌细胞中与凋亡相关的 Bcl-2 相互作用的细胞死亡介体（BIM）的上调，从而诱导细胞凋亡。BIM 的 RNA 干扰（RNAi）介导的耗竭抑制了拉帕替尼诱导的凋亡，这表明 BIM 的诱导在这个过程中起作用。与没有 PIK3CA 突变的细胞相比，具有 PIK3CA 突变的细胞中，拉帕替尼的促凋亡作用不那么明显。拉帕替尼未能抑制 PIK3CA 突变细胞中 AKT 的磷酸化，这可能是由于突变导致磷脂酰肌醇 3-激酶（PI3K）信号通路的过度激活。PI3K 的催化亚基 PIK3CA 的耗竭表明，在这些细胞中，survivin 的表达受 PI3K 通路的调节，这表明 PI3K-survivin 信号通路的抑制不足是导致 PIK3CA 突变的 HER2 扩增阳性细胞中拉帕替尼促凋亡作用有限的原因。与这一观点一致的是，RNAi 耗竭 survivin 或用 PI3K 抑制剂处理可显著增加用拉帕替尼处理的 PIK3CA 突变细胞中的凋亡水平。我们的研究结果表明，抑制 PI3K-survivin 和 MEK-ERK-BIM 通路对于有效诱导 HER2 扩增的乳腺癌细胞凋亡是必需的。
