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Decoupling of the PI3K Pathway via Mutation Necessitates Combinatorial Treatment in HER2+ Breast Cancer
James E Korkola1, Eric A Collisson2, Laura Heiser1
1Oregon Health Sciences University, Department of Biomedical Engineering, Portland, Oregon, United States of America.
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(+)/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.
Insights
Combining lapatinib with AKT inhibitors (AKTi) shows synergy in HER2-positive breast cancers with PIK3CA mutations. This combination effectively targets signaling pathways, unlike in tumors with wild-type PIK3CA.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- HER2-positive breast cancer remains a significant challenge.
- Targeting both HER2 and AKT pathways is a potential therapeutic strategy.
- PIK3CA mutations influence treatment response in HER2-positive breast cancer.
Purpose of the Study:
- To determine the optimal combination of HER2 and AKT inhibitors in HER2-positive breast cancer.
- To investigate the role of PIK3CA mutations in response to lapatinib and AKT inhibitors (AKTi).
- To elucidate the underlying signaling dynamics of combination therapy.
Main Methods:
- Assessed cellular and molecular responses to lapatinib and two AKTi (GSK690693, GSK2141795) in 22 HER2-positive breast cancer cell lines.
- Analyzed phospho-protein levels in 15 cell lines after drug treatment.
- Utilized a nonlinear ordinary differential equation model to simulate signaling pathways.
- Investigated responses in HER2-positive SKBR3 cells transfected with PIK3CA variants.
Main Results:
- Lapatinib plus AKTi combination therapy demonstrated synergistic effects in HER2-positive/PIK3CA-mutant cell lines, but not in HER2-positive/PIK3CA-wild-type cell lines.
- Lapatinib treatment alone showed less attenuation of p-S6RP levels in PIK3CA-mutant cells.
- Combination therapy effectively reduced p-S6RP levels and blunted compensatory upregulation of p-HER3 and p-HER2 in PIK3CA-mutant cells.
- Mathematical modeling supported that PIK3CA mutations blunt lapatinib's inhibition of AKT signaling, which can be overcome by combination therapy.
Conclusions:
- The combination of lapatinib and AKTi is a promising strategy for HER2-positive breast cancers with PIK3CA mutations.
- PIK3CA mutations confer resistance to lapatinib by activating AKT signaling.
- Combination therapy with lapatinib and AKTi can overcome resistance mediated by PIK3CA mutations.
- This combination offers limited additional benefit in HER2-positive/PIK3CA-wild-type breast cancer.
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