Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129.
Proc Natl Acad Sci U S A. 2013 Dec 24;110(52):21124-9. doi: 10.1073/pnas.1314124110. Epub 2013 Dec 10.
The PI3K pathway is genetically altered in excess of 70% of breast cancers, largely through PIK3CA mutation and HER2 amplification. Preclinical studies have suggested that these subsets of breast cancers are particularly sensitive to PI3K inhibitors; however, the reasons for this heightened sensitivity are mainly unknown. We investigated the signaling effects of PI3K inhibition in PIK3CA mutant and HER2 amplified breast cancers using PI3K inhibitors currently in clinical trials. Unexpectedly, we found that in PIK3CA mutant and HER2 amplified breast cancers sensitive to PI3K inhibitors, PI3K inhibition led to a rapid suppression of Rac1/p21-activated kinase (PAK)/protein kinase C-RAF (C-RAF)/ protein kinase MEK (MEK)/ERK signaling that did not involve RAS. Furthermore, PI3K inhibition led to an ERK-dependent up-regulation of the proapoptotic protein, BIM, followed by induction of apoptosis. Expression of a constitutively active form of Rac1 in these breast cancer models blocked PI3Ki-induced down-regulation of ERK phosphorylation, apoptosis, and mitigated PI3K inhibitor sensitivity in vivo. In contrast, protein kinase AKT inhibitors failed to block MEK/ERK signaling, did not up-regulate BIM, and failed to induce apoptosis. Finally, we identified phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 (P-Rex1) as the PI(3,4,5)P3-dependent guanine exchange factor for Rac1 responsible for regulation of the Rac1/C-RAF/MEK/ERK pathway in these cells. The expression level of P-Rex1 correlates with sensitivity to PI3K inhibitors in these breast cancer cell lines. Thus, PI3K inhibitors have enhanced activity in PIK3CA mutant and HER2 amplified breast cancers in which PI3K inhibition down-regulates both the AKT and Rac1/ERK pathways. In addition, P-Rex1 may serve as a biomarker to predict response to single-agent PI3K inhibitors within this subset of breast cancers.
PI3K 通路在超过 70%的乳腺癌中发生遗传改变，主要通过 PIK3CA 突变和 HER2 扩增。临床前研究表明，这些乳腺癌亚群对 PI3K 抑制剂特别敏感；然而，这种敏感性增强的原因主要未知。我们使用目前正在临床试验中的 PI3K 抑制剂研究了 PI3K 抑制对 PIK3CA 突变和 HER2 扩增乳腺癌的信号作用。出乎意料的是，我们发现，在对 PI3K 抑制剂敏感的 PIK3CA 突变和 HER2 扩增乳腺癌中，PI3K 抑制导致 Rac1/p21 激活激酶 (PAK)/蛋白激酶 C-RAF (C-RAF)/蛋白激酶 MEK (MEK)/细胞外信号调节激酶 (ERK) 信号的快速抑制，而不涉及 RAS。此外，PI3K 抑制导致 ERK 依赖性上调促凋亡蛋白 BIM，随后诱导细胞凋亡。在这些乳腺癌模型中表达组成型激活形式的 Rac1 可阻断 PI3Ki 诱导的 ERK 磷酸化下调、凋亡和体内减轻 PI3K 抑制剂敏感性。相比之下，蛋白激酶 AKT 抑制剂不能阻断 MEK/ERK 信号，不能上调 BIM，也不能诱导细胞凋亡。最后，我们确定了磷脂酰肌醇 3,4,5-三磷酸依赖性 Rac 交换因子 1 (P-Rex1) 是负责调节这些细胞中 Rac1/C-RAF/MEK/ERK 通路的 PI(3,4,5)P3 依赖性鸟嘌呤交换因子。P-Rex1 的表达水平与这些乳腺癌细胞系对 PI3K 抑制剂的敏感性相关。因此，PI3K 抑制剂在 PIK3CA 突变和 HER2 扩增乳腺癌中具有增强的活性，在这些乳腺癌中，PI3K 抑制下调 AKT 和 Rac1/ERK 通路。此外，P-Rex1 可能作为预测该亚组乳腺癌对单药 PI3K 抑制剂反应的生物标志物。
