Department of Medicine, Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, and Vanderbilt University Institute of Imaging Sciences, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):5021-6. doi: 10.1073/pnas.1016140108. Epub 2011 Mar 8.
Sustained and complete inhibition of HER3 and its output to PI3K/Akt are required for the optimal antitumor effect of therapeutic inhibitors of the HER2 oncogene. Here, we show that, after inhibition of the HER2 tyrosine kinase with lapatinib, there is PI3K/Akt and FoxO3a-dependent up-regulation of HER3 mRNA and protein. Up-regulated HER3 was then phosphorylated by residual HER2 activity, thus partially maintaining P-Akt and limiting the antitumor action of lapatinib. Inhibition of HER3 with siRNA or a neutralizing HER3 antibody sensitized HER2+ breast cancer cells and xenografts to lapatinib both in vitro and in vivo. Combined blockade of HER2 and HER3 inhibited pharmacodynamic biomarkers of PI3K/Akt activity more effectively than each inhibitor alone. These results suggest that because of HER3-mediated compensation, current clinical inhibitors of HER2 and PI3K/Akt will not block the PI3K pathway completely. They also suggest that therapeutic inhibitors of HER3 should be used in combination with HER2 inhibitors and PI3K pathway inhibitors in patients with HER2- and PI3K-dependent cancers.
需要持续且完全抑制 HER3 及其对 PI3K/Akt 的作用，才能发挥治疗性 HER2 致癌基因抑制剂的最佳抗肿瘤效果。本文表明，在 lapatinib 抑制 HER2 酪氨酸激酶后，会出现 PI3K/Akt 和 FoxO3a 依赖性的 HER3 mRNA 和蛋白上调。上调的 HER3 随后被残留的 HER2 活性磷酸化，从而部分维持 P-Akt，并限制 lapatinib 的抗肿瘤作用。用 siRNA 或中和 HER3 抗体抑制 HER3，可在体外和体内使 HER2+乳腺癌细胞和异种移植物对 lapatinib 敏感。与每种抑制剂单独使用相比，联合阻断 HER2 和 HER3 可更有效地抑制 PI3K/Akt 活性的药效生物标志物。这些结果表明，由于 HER3 介导的代偿作用，目前针对 HER2 和 PI3K/Akt 的临床抑制剂不会完全阻断 PI3K 通路。它们还表明，针对 HER3 的治疗性抑制剂应与 HER2 抑制剂和 PI3K 通路抑制剂联合用于 HER2 和 PI3K 依赖性癌症患者。
