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Title: Decoupling of the PI3K pathway via mutation necessitates combinatorial treatment in HER2+ breast cancer

We report here on experimental and theoretical efforts to determine how best to combine drugs that inhibit HER2 and AKT in HER2+ breast cancers. We accomplished this by measuring cellular and molecular responses to lapatinib and the AKT inhibitors (AKTi) GSK690693 and GSK2141795 in a panel of 22 HER2+ breast cancer cell lines carrying wild type or mutant PIK3CA. We observed that combinations of lapatinib plus AKTi were synergistic in HER2/PIK3CAmut cell lines but not in HER2+/PIK3CAwt cell lines. We measured changes in phospho-protein levels in 15 cell lines after treatment with lapatinib, AKTi or lapatinib + AKTi to shed light on the underlying signaling dynamics. This revealed that p-S6RP levels were less well attenuated by lapatinib in HER2+/PIK3CAmut cells compared to HER2+/PIK3CAwt cells and that lapatinib + AKTi reduced p-S6RP levels to those achieved in HER2+/PIK3CAwt cells with lapatinib alone. We also found that that compensatory up-regulation of p-HER3 and p-HER2 is blunted in PIK3CAmut cells following lapatinib + AKTi treatment. Responses of HER2+ SKBR3 cells transfected with lentiviruses carrying control or PIK3CAmut sequences were similar to those observed in HER2+/PIK3CAmut cell lines but not in HER2+/PIK3CAwt cell lines. We used a nonlinear ordinary differential equation model to supportmore » the idea that PIK3CA mutations act as downstream activators of AKT that blunt lapatinib inhibition of downstream AKT signaling and that the effects of PIK3CA mutations can be countered by combining lapatinib with an AKTi. This combination does not confer substantial benefit beyond lapatinib in HER2+/PIK3CAwt cells.« less
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  1. Oregon Health Sciences Univ., Portland, OR (United States)
  2. Univ. of California San Francisco, San Francisco, CA (United States)
  3. Netherlands Cancer Institute, Amsterdam (The Netherlands); Univ. of Warwick, Coventry (United Kingdom)
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  5. Univ. of California, Berkeley, CA (United States)
  6. Oregon Health Sciences Univ., Portland, OR (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  7. MD Anderson Cancer Center, Houston, TX (United States)
  8. Netherlands Cancer Institute, Amsterdam (The Netherlands); German Center for Neurodegenerative Diseases, Bonn (Germany)
  9. Univ. of Texas, Houston, TX (United States). MD Anderson Cancer Center.
Publication Date:
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Accepted Manuscript
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Additional Journal Information:
Journal Volume: 10; Journal Issue: 7; Journal ID: ISSN 1932-6203
Public Library of Science
Research Org:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Org:
USDOE; National Institutes of Health, National Cancer Institute
Country of Publication:
United States
60 APPLIED LIFE SCIENCES breast cancer; cancer treatment; drug therapy; MAPK signaling cascades; signal inhibition; AKT signaling cascade; confidence intervals; drug interactions