Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Cancer Cell. 2015 Jan 12;27(1):109-22. doi: 10.1016/j.ccell.2014.11.008. Epub 2014 Dec 24.
In PTEN-mutated tumors, we show that PI3Kα activity is suppressed and PI3K signaling is driven by PI3Kβ. A selective inhibitor of PI3Kβ inhibits the Akt/mTOR pathway in these tumors but not in those driven by receptor tyrosine kinases. However, inhibition of PI3Kβ only transiently inhibits Akt/mTOR signaling because it relieves feedback inhibition of IGF1R and other receptors and thus causes activation of PI3Kα and a rebound in downstream signaling. This rebound is suppressed and tumor growth inhibition enhanced with combined inhibition of PI3Kα and PI3Kβ. In PTEN-deficient models of prostate cancer, this effective inhibition of PI3K causes marked activation of androgen receptor activity. Combined inhibition of both PI3K isoforms and androgen receptor results in major tumor regressions.
在 PTEN 突变的肿瘤中，我们表明 PI3Kα 的活性受到抑制，而 PI3K 信号通路由 PI3Kβ 驱动。PI3Kβ 的选择性抑制剂可抑制这些肿瘤中的 Akt/mTOR 通路，但不抑制由受体酪氨酸激酶驱动的肿瘤中的 Akt/mTOR 通路。然而，PI3Kβ 的抑制仅能短暂抑制 Akt/mTOR 信号通路，因为它解除了 IGF1R 和其他受体的反馈抑制，从而导致 PI3Kα 的激活和下游信号的反弹。这种反弹可通过联合抑制 PI3Kα 和 PI3Kβ 来抑制，并增强肿瘤生长抑制作用。在缺乏 PTEN 的前列腺癌模型中，这种有效的 PI3K 抑制导致雄激素受体活性的显著激活。联合抑制两种 PI3K 同工型和雄激素受体可导致肿瘤明显消退。
