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

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Journal Article
PLoS ONE, 2015, 10 (7)
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© 2015 Korkola et al. 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+/PIK3CAmutcell lines but not in HER2+/PIK3CAwtcell lines. We measured changes in phospho-protein levels in 15 cell lines after treatment with lapatinib, AKTior lapatinib + AKTito shed light on the underlying signaling dynamics. This revealed that p- S6RP levels were less well attenuated by lapatinib in HER2+/PIK3CAmutcells compared to HER2+/PIK3CAwtcells and that lapatinib + AKTireduced p-S6RP levels to those achieved in HER2+/PIK3CAwtcells with lapatinib alone. We also found that that compensatory upregulation of p-HER3 and p-HER2 is blunted in PIK3CAmutcells following lapatinib + AKTitreatment. Responses of HER2+SKBR3 cells transfected with lentiviruses carrying control or PIK3CAmutsequences were similar to those observed in HER2+/PIK3CAmutcell lines but not in HER2+/PIK3CAwtcell 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+/PIK3CAwtcells. Copyright:
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