Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.
Cancer Cell. 2015 Jan 12;27(1):97-108. doi: 10.1016/j.ccell.2014.11.007. Epub 2014 Dec 24.
BYL719, which selectively inhibits the alpha isoform of the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (p110a), is currently in clinical trials for the treatment of solid tumors, especially luminal breast cancers with PIK3CA mutations and/or HER2 amplification. This study reveals that, even among these sensitive cancers, the initial efficacy of p110α inhibition is mitigated by rapid re-accumulation of the PI3K product PIP3 produced by the p110β isoform. Importantly, the reactivation of PI3K mediated by p110β does not invariably restore AKT phosphorylation, demonstrating the limitations of using phospho-AKT as a surrogate to measure PI3K activation. Consistently, we show that the addition of the p110β inhibitor to BYL719 prevents the PIP3 rebound and induces greater antitumor efficacy in HER2-amplified and PIK3CA mutant cancers.
BYL719 选择性抑制磷酸肌醇 3-激酶 (PI3K) 催化亚基 (p110a) 的α 同工型，目前正在临床试验中用于治疗实体瘤，特别是具有 PIK3CA 突变和/或 HER2 扩增的腔乳腺癌。本研究表明，即使在这些敏感的癌症中，p110β 同工型产生的 PI3K 产物 PIP3 的快速再积累也减轻了 p110α 抑制的初始疗效。重要的是，p110β 介导的 PI3K 的重新激活并不总是恢复 AKT 磷酸化，这表明使用磷酸化 AKT 作为替代物来测量 PI3K 激活存在局限性。一致地，我们表明，将 p110β 抑制剂添加到 BYL719 中可防止 PIP3 反弹，并在 HER2 扩增和 PIK3CA 突变型癌症中诱导更大的抗肿瘤疗效。
