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应答的预测性和药效生物标志物。

PI3K信号通路充当调节细胞存活，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，从而导致PI3K途径的组成型激活。使用无偏细胞系筛选方法，我们测试了乳腺癌细胞系对taselisib（一种有效的PI3K抑制剂）的敏感性，并将其与关键生物标志物（PIK3CA，HER2，PTEN和ESR1）相关。我们进一步评估了taselisib如何在乳腺癌中发生的不同基因组背景中调节下游信号传导。我们发现对taselisib的敏感性与PIK3CA突变的存在有关，但与HER2状态无关。我们进一步显示，与HER2扩增的/ PIK3CA突变细胞系相比，HER2扩增的/ PIK3CA野生型细胞系对taselisib的敏感性不高。在PIK3CA突变体/ PTEN无背景下，在存在taselisib的情况下PI3K下游信号回弹，这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的雌激素受体（ER; ESR1）突变同时发生。但是，ESR1突变与PIK3CA突变的共存在单药或与氟维司群合用时均不会影响对taselisib的反应。总而言之，这些数据表明，taselisib在乳腺癌中的发生应在PIK3CA突变的环境中进行，并由研究中的特定亚型决定共同治疗。