Experimental Therapeutics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Pg Vall d'Hebron, Barcelona, Spain.
Cancer Discov. 2012 Nov;2(11):1036-47. doi: 10.1158/2159-8290.CD-11-0348. Epub 2012 Aug 22.
PARP inhibitors are active in tumors with defects in DNA homologous recombination (HR) due to BRCA1/2 mutations. The phosphoinositide 3-kinase (PI3K) signaling pathway preserves HR steady state. We hypothesized that in BRCA-proficient triple-negative breast cancer (TNBC), PI3K inhibition would result in HR impairment and subsequent sensitization to PARP inhibitors. We show in TNBC cells that PI3K inhibition leads to DNA damage, downregulation of BRCA1/2, gain in poly-ADP-ribosylation, and subsequent sensitization to PARP inhibition. In TNBC patient-derived primary tumor xenografts, dual PI3K and PARP inhibition with BKM120 and olaparib reduced the growth of tumors displaying BRCA1/2 downregulation following PI3K inhibition. PI3K-mediated BRCA downregulation was accompanied by extracellular signal-regulated kinase (ERK) phosphorylation. Overexpression of an active form of MEK1 resulted in ERK activation and downregulation of BRCA1, whereas the MEK inhibitor AZD6244 increased BRCA1/2 expression and reversed the effects of MEK1. We subsequently identified that the ETS1 transcription factor was involved in the ERK-dependent BRCA1/2 downregulation and that knockdown of ETS1 led to increased BRCA1/2 expression, limiting the sensitivity to combined BKM120 and olaparib in 3-dimensional culture.
Treatment options are limited for patients with TNBCs. PARP inhibitors have clinical activity restricted to a small subgroup of patients with BRCA mutations. Here, we show that PI3K blockade results in HR impairment and sensitization to PARP inhibition in TNBCs without BRCA mutations, providing a rationale to combine PI3K and PARP inhibitors in this indication. Our findings could greatly expand the number of patients with breast cancer that would benefit from therapy with PARP inhibitors. On the basis of our findings, a clinical trial with BKM120 and olaparib is being initiated in patients with TNBCs.
聚腺苷二磷酸核糖聚合酶（PARP）抑制剂在因 BRCA1/2 突变而存在 DNA 同源重组（HR）缺陷的肿瘤中具有活性。磷酸肌醇 3-激酶（PI3K）信号通路维持 HR 的稳定状态。我们假设在 BRCA 功能正常的三阴性乳腺癌（TNBC）中，PI3K 抑制将导致 HR 损伤，随后对 PARP 抑制剂敏感。我们在 TNBC 细胞中表明，PI3K 抑制导致 DNA 损伤、BRCA1/2 下调、多聚 ADP-核糖化增加，随后对 PARP 抑制敏感。在 TNBC 患者来源的原发性肿瘤异种移植模型中，BKM120 和奥拉帕利的双重 PI3K 和 PARP 抑制减少了 PI3K 抑制后显示 BRCA1/2 下调的肿瘤的生长。PI3K 介导的 BRCA 下调伴随着细胞外信号调节激酶（ERK）磷酸化。组成型激活形式的 MEK1 的过表达导致 ERK 激活和 BRCA1 的下调，而 MEK 抑制剂 AZD6244 增加 BRCA1/2 的表达并逆转 MEK1 的作用。我们随后确定 ETS1 转录因子参与 ERK 依赖性 BRCA1/2 下调，并且 ETS1 的敲低导致 BRCA1/2 表达增加，限制了在 3 维培养中对联合 BKM120 和奥拉帕利的敏感性。
对于 TNBC 患者，治疗选择有限。PARP 抑制剂的临床活性仅限于一小部分具有 BRCA 突变的患者。在这里，我们表明，在没有 BRCA 突变的 TNBC 中，PI3K 阻断导致 HR 损伤和对 PARP 抑制剂敏感，为在该适应症中联合使用 PI3K 和 PARP 抑制剂提供了依据。我们的发现可能会极大地扩大受益于 PARP 抑制剂治疗的乳腺癌患者数量。基于我们的发现，一项在 TNBC 患者中使用 BKM120 和奥拉帕利的临床试验正在启动。
