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 H...
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doaj-01e6b6cfbd714bc98c36f3440a8d060c2020-11-25T01:46:09ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01107e013321910.1371/journal.pone.0133219Decoupling of the PI3K Pathway via Mutation Necessitates Combinatorial Treatment in HER2+ Breast Cancer.James E KorkolaEric A CollissonLaura HeiserChris OatesNora BayaniSleiman ItaniAmanda EschWallace ThompsonObi L GriffithNicholas J WangWen-Lin KuoBrian CooperJessica BilligSafiyyah ZiyadJenny L HungLakshmi JakkulaHeidi FeilerYiling LuGordon B MillsPaul T SpellmanClaire TomlinSach MukherjeeJoe W GrayWe 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(+)/PIK3CA(mut) cell lines but not in HER2(+)/PIK3CA(wt) 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(+)/PIK3CA(mut) cells compared to HER2(+)/PIK3CAwt cells and that lapatinib + AKTi reduced p-S6RP levels to those achieved in HER2(+)/PIK3CA(wt) cells with lapatinib alone. We also found that that compensatory up-regulation of p-HER3 and p-HER2 is blunted in PIK3CA(mut) cells following lapatinib + AKTi treatment. Responses of HER2(+) SKBR3 cells transfected with lentiviruses carrying control or PIK3CA(mut )sequences were similar to those observed in HER2(+)/PIK3CA(mut) cell lines but not in HER2(+)/PIK3CA(wt) 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+/PIK3CA(wt) cells.http://europepmc.org/articles/PMC4504492?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
James E Korkola Eric A Collisson Laura Heiser Chris Oates Nora Bayani Sleiman Itani Amanda Esch Wallace Thompson Obi L Griffith Nicholas J Wang Wen-Lin Kuo Brian Cooper Jessica Billig Safiyyah Ziyad Jenny L Hung Lakshmi Jakkula Heidi Feiler Yiling Lu Gordon B Mills Paul T Spellman Claire Tomlin Sach Mukherjee Joe W Gray |
spellingShingle |
James E Korkola Eric A Collisson Laura Heiser Chris Oates Nora Bayani Sleiman Itani Amanda Esch Wallace Thompson Obi L Griffith Nicholas J Wang Wen-Lin Kuo Brian Cooper Jessica Billig Safiyyah Ziyad Jenny L Hung Lakshmi Jakkula Heidi Feiler Yiling Lu Gordon B Mills Paul T Spellman Claire Tomlin Sach Mukherjee Joe W Gray Decoupling of the PI3K Pathway via Mutation Necessitates Combinatorial Treatment in HER2+ Breast Cancer. PLoS ONE |
author_facet |
James E Korkola Eric A Collisson Laura Heiser Chris Oates Nora Bayani Sleiman Itani Amanda Esch Wallace Thompson Obi L Griffith Nicholas J Wang Wen-Lin Kuo Brian Cooper Jessica Billig Safiyyah Ziyad Jenny L Hung Lakshmi Jakkula Heidi Feiler Yiling Lu Gordon B Mills Paul T Spellman Claire Tomlin Sach Mukherjee Joe W Gray |
author_sort |
James E Korkola |
title |
Decoupling of the PI3K Pathway via Mutation Necessitates Combinatorial Treatment in HER2+ Breast Cancer. |
title_short |
Decoupling of the PI3K Pathway via Mutation Necessitates Combinatorial Treatment in HER2+ Breast Cancer. |
title_full |
Decoupling of the PI3K Pathway via Mutation Necessitates Combinatorial Treatment in HER2+ Breast Cancer. |
title_fullStr |
Decoupling of the PI3K Pathway via Mutation Necessitates Combinatorial Treatment in HER2+ Breast Cancer. |
title_full_unstemmed |
Decoupling of the PI3K Pathway via Mutation Necessitates Combinatorial Treatment in HER2+ Breast Cancer. |
title_sort |
decoupling of the pi3k pathway via mutation necessitates combinatorial treatment in her2+ breast cancer. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2015-01-01 |
description |
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(+)/PIK3CA(mut) cell lines but not in HER2(+)/PIK3CA(wt) 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(+)/PIK3CA(mut) cells compared to HER2(+)/PIK3CAwt cells and that lapatinib + AKTi reduced p-S6RP levels to those achieved in HER2(+)/PIK3CA(wt) cells with lapatinib alone. We also found that that compensatory up-regulation of p-HER3 and p-HER2 is blunted in PIK3CA(mut) cells following lapatinib + AKTi treatment. Responses of HER2(+) SKBR3 cells transfected with lentiviruses carrying control or PIK3CA(mut )sequences were similar to those observed in HER2(+)/PIK3CA(mut) cell lines but not in HER2(+)/PIK3CA(wt) 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+/PIK3CA(wt) cells. |
url |
http://europepmc.org/articles/PMC4504492?pdf=render |
work_keys_str_mv |
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