期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 12, 页码 5021-5026出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1016140108
关键词
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资金
- R01 Grants [CA80195, CA121210, K25 CA127349]
- American Cancer Society (ACS) [CRP-07-234]
- Lee Jeans Translational Breast Cancer Research Program
- Breast Cancer Specialized Program of Research Excellence (SPORE) [P50 CA98131]
- National Cancer Institute [U24 CA126588]
- Vanderbilt-Ingram Cancer Center [P30 CA68485]
- ACS [118813-PF-10-070-01-TBG]
- DOD [BC093376]
- Cancer Research Dream Team Translational Cancer Research Grant [SU2C-AACR-DT0209]
- [T32DK007563]
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 bio-markers 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.
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