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

Abstract

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

Authors:
 [1];  [2];  [1];  [3];  [4];  [5];  [1];  [1];  [4];  [1];  [4];  [4];  [4];  [4];  [4];  [4];  [6];  [7];  [7];  [1] more »;  [5];  [8];  [1];  [9] « less
+ Show Author Affiliations
  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:
Research Org.:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE; National Cancer Institute (NCI)
OSTI Identifier:
1212476
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Volume: 10; Journal Issue: 7; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; breast cancer; cancer treatment; drug therapy; MAPK signaling cascades; signal inhibition; AKT signaling cascade; confidence intervals; drug interactions

Citation Formats

Korkola, James E., Collisson, Eric A., Heiser, Laura, Oates, Chris, Bayani, Nora, Itani, Sleiman, Esch, Amanda, Thompson, Wallace, Griffith, Obi L., Wang, Nicholas J., Kuo, Wen -Lin, Cooper, Brian, Billig, Jessica, Ziyad, Safiyyah, Hung, Jenny L., Jakkula, Lakshmi, Feiler, Heidi, Lu, Yiling, Mills, Gordon B., Spellman, Paul T., Tomlin, Claire, Mukherjee, Sach, Gray, Joe W., and Wong, Kwong -Kwok. Decoupling of the PI3K pathway via mutation necessitates combinatorial treatment in HER2+ breast cancer. United States: N. p., 2015. Web. doi:10.1371/journal.pone.0133219.
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Korkola, James E., Collisson, Eric A., Heiser, Laura, Oates, Chris, Bayani, Nora, Itani, Sleiman, Esch, Amanda, Thompson, Wallace, Griffith, Obi L., Wang, Nicholas J., Kuo, Wen -Lin, Cooper, Brian, Billig, Jessica, Ziyad, Safiyyah, Hung, Jenny L., Jakkula, Lakshmi, Feiler, Heidi, Lu, Yiling, Mills, Gordon B., Spellman, Paul T., Tomlin, Claire, Mukherjee, Sach, Gray, Joe W., & Wong, Kwong -Kwok. Decoupling of the PI3K pathway via mutation necessitates combinatorial treatment in HER2+ breast cancer. United States. https://doi.org/10.1371/journal.pone.0133219
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Korkola, James E., Collisson, Eric A., Heiser, Laura, Oates, Chris, Bayani, Nora, Itani, Sleiman, Esch, Amanda, Thompson, Wallace, Griffith, Obi L., Wang, Nicholas J., Kuo, Wen -Lin, Cooper, Brian, Billig, Jessica, Ziyad, Safiyyah, Hung, Jenny L., Jakkula, Lakshmi, Feiler, Heidi, Lu, Yiling, Mills, Gordon B., Spellman, Paul T., Tomlin, Claire, Mukherjee, Sach, Gray, Joe W., and Wong, Kwong -Kwok. Thu . "Decoupling of the PI3K pathway via mutation necessitates combinatorial treatment in HER2+ breast cancer". United States. https://doi.org/10.1371/journal.pone.0133219. https://www.osti.gov/servlets/purl/1212476.
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@article{osti_1212476,
title = {Decoupling of the PI3K pathway via mutation necessitates combinatorial treatment in HER2+ breast cancer},
author = {Korkola, James E. and Collisson, Eric A. and Heiser, Laura and Oates, Chris and Bayani, Nora and Itani, Sleiman and Esch, Amanda and Thompson, Wallace and Griffith, Obi L. and Wang, Nicholas J. and Kuo, Wen -Lin and Cooper, Brian and Billig, Jessica and Ziyad, Safiyyah and Hung, Jenny L. and Jakkula, Lakshmi and Feiler, Heidi and Lu, Yiling and Mills, Gordon B. and Spellman, Paul T. and Tomlin, Claire and Mukherjee, Sach and Gray, Joe W. and Wong, Kwong -Kwok},
abstractNote = {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 support 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.},
doi = {10.1371/journal.pone.0133219},
journal = {PLoS ONE},
number = 7,
volume = 10,
place = {United States},
year = {Thu Jul 16 00:00:00 EDT 2015},
month = {Thu Jul 16 00:00:00 EDT 2015}
}
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https://doi.org/10.1371/journal.pone.0133219
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Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3
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    Works referencing / citing this record:

    Delineating feedback activity in the MAPK and AKT pathways using feedback-enabled Inference of Signaling Activity
    posted_content, February 2018

    • Thijssen, Bram; Jastrzebski, Katarzyna; Beijersbergen, Roderick L.
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    GRB7 dependent proliferation of basal‐like, HER‐2 positive human breast cancer cell lines is mediated in part by HER‐1 signaling
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    • Luoh, Shiuh‐Wen; Wagoner, Wendy; Wang, Xiaoyan
    • Molecular Carcinogenesis, Vol. 58, Issue 5
    • DOI: 10.1002/mc.22963

    Microenvironment-Mediated Mechanisms of Resistance to HER2 Inhibitors Differ between HER2+ Breast Cancer Subtypes
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    Quantitative, in situ analysis of mRNAs and proteins with subcellular resolution
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