Experimental Therapeutics Program, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Oncogene. 2011 Jun 2;30(22):2547-57. doi: 10.1038/onc.2010.626. Epub 2011 Jan 31.
There is a strong rationale to therapeutically target the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway in breast cancer since it is highly deregulated in this disease and it also mediates resistance to anti-HER2 therapies. However, initial studies with rapalogs, allosteric inhibitors of mTORC1, have resulted in limited clinical efficacy probably due to the release of a negative regulatory feedback loop that triggers AKT and ERK signaling. Since activation of AKT occurs via PI3K, we decided to explore whether PI3K inhibitors prevent the activation of these compensatory pathways. Using HER2-overexpressing breast cancer cells as a model, we observed that PI3K inhibitors abolished AKT activation. However, PI3K inhibition resulted in a compensatory activation of the ERK signaling pathway. This enhanced ERK signaling occurred as a result of activation of HER family receptors as evidenced by induction of HER receptors dimerization and phosphorylation, increased expression of HER3 and binding of adaptor molecules to HER2 and HER3. The activation of ERK was prevented with either MEK inhibitors or anti-HER2 monoclonal antibodies and tyrosine kinase inhibitors. Combined administration of PI3K inhibitors with either HER2 or MEK inhibitors resulted in decreased proliferation, enhanced cell death and superior anti-tumor activity compared with single agent PI3K inhibitors. Our findings indicate that PI3K inhibition in HER2-overexpressing breast cancer activates a new compensatory pathway that results in ERK dependency. Combined anti-MEK or anti-HER2 therapy with PI3K inhibitors may be required in order to achieve optimal efficacy in HER2-overexpressing breast cancer. This approach warrants clinical evaluation.
在乳腺癌中，针对磷脂酰肌醇 3-激酶/蛋白激酶 B/雷帕霉素靶蛋白（PI3K/AKT/mTOR）途径进行治疗具有很强的理论基础，因为该途径在这种疾病中高度失调，并且它还介导对抗 HER2 治疗的耐药性。然而，用 rapalog（mTORC1 的别构抑制剂）进行的初步研究导致临床疗效有限，可能是由于触发 AKT 和 ERK 信号的负反馈调节环的释放。由于 AKT 的激活是通过 PI3K 发生的，我们决定探讨 PI3K 抑制剂是否可以阻止这些补偿途径的激活。使用过表达 HER2 的乳腺癌细胞作为模型，我们观察到 PI3K 抑制剂可消除 AKT 的激活。然而，PI3K 抑制导致 ERK 信号通路的代偿性激活。这种增强的 ERK 信号发生是由于 HER 家族受体的激活，这可通过诱导 HER 受体二聚化和磷酸化、HER3 表达增加以及衔接分子与 HER2 和 HER3 的结合来证明。ERK 的激活可以被 MEK 抑制剂或抗 HER2 单克隆抗体和酪氨酸激酶抑制剂阻止。PI3K 抑制剂与 HER2 或 MEK 抑制剂联合给药可导致与单一 PI3K 抑制剂相比，增殖减少、细胞死亡增加和抗肿瘤活性增强。我们的研究结果表明，在过表达 HER2 的乳腺癌中，PI3K 抑制会激活新的补偿途径，从而导致 ERK 依赖性。为了在过表达 HER2 的乳腺癌中实现最佳疗效，可能需要联合使用 MEK 或抗 HER2 疗法与 PI3K 抑制剂。这种方法值得临床评估。
