The PI3K signaling pathway serves as a central node in regulating cell survival, proliferation, and metabolism. PIK3CA, the gene encoding the PI3K catalytic subunit p110-alpha, is commonly altered in breast cancer resulting in the constitutive activation of the PI3K pathway. Using an unbiased cell line screening approach, we tested the sensitivity of breast cancer cell lines to taselisib, a potent PI3K inhibitor, and correlated sensitivity with key biomarkers (PIK3CA, HER2, PTEN, and ESR1). We further assessed how taselisib modulates downstream signaling in the different genomic backgrounds that occur within breast cancer. We found that sensitivity to taselisib correlated with the presence of PIK3CA mutations, but was independent of HER2 status. We further showed that HER2-amplified/PIK3CA wild-type cell lines are not as sensitive to taselisib when compared with HER2-amplified/PIK3CA-mutant cell lines. In a PIK3CA-mutant/PTEN null background, PI3K downstream signaling rebounded in the presence of taselisib correlating with decreased sensitivity at later time points. Finally, we observed that PIK3CA mutations cooccurred with mutations in the estrogen receptor (ER; ESR1) in metastatic tumors from patients with ER+ breast cancer. However, the cooccurrence of an ESR1 mutation with a PIK3CA mutation did not affect response to taselisib in a single agent setting or in combination with fulvestrant. In summary, these data suggest that development of taselisib in breast cancer should occur in a PIK3CA-mutant setting with cotreatments determined by the specific subtypes under investigation.

中文翻译：

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在乳腺癌临床前模型中对磷脂酰肌醇 3-激酶抑制剂 Taselisib 反应的预测和药效学生物标志物

PI3K 信号通路作为调节细胞存活、增殖和代谢的中心节点。PIK3CA 是编码 PI3K 催化亚基 p110-alpha 的基因，通常在乳腺癌中发生改变，导致 PI3K 通路的组成型激活。我们使用无偏见的细胞系筛选方法，测试了乳腺癌细胞系对 taselisib（一种有效的 PI3K 抑制剂）的敏感性，以及与关键生物标志物（PIK3CA、HER2、PTEN 和 ESR1）的相关敏感性。我们进一步评估了 taselisib 如何在乳腺癌内发生的不同基因组背景中调节下游信号。我们发现对 taselisib 的敏感性与 PIK3CA 突变的存在相关，但与 HER2 状态无关。我们进一步表明，与 HER2 扩增/PIK3CA 突变细胞系相比，HER2 扩增/PIK3CA 野生型细胞系对 taselisib 不那么敏感。在 PIK3CA 突变体/PTEN 无效背景中，PI3K 下游信号在存在 taselisib 的情况下反弹，与稍后时间点的敏感性降低相关。最后，我们观察到 PIK3CA 突变与 ER+ 乳腺癌患者转移性肿瘤中雌激素受体（ER；ESR1）的突变同时发生。然而，ESR1 突变与 PIK3CA 突变的同时发生并没有影响在单一药物设置或与氟维司群组合中对 taselisib 的反应。总之，这些数据表明，taselisib 在乳腺癌中的发展应该发生在 PIK3CA 突变环境中，并由正在研究的特定亚型确定联合治疗。