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 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.
Highlights
Genome aberration targeted therapies promise greater efficacy and fewer potential side effects than traditional chemotherapeutics for the treatment of advanced cancers
The doses to inhibit growth by 50% (GI50) and to achieve total growth inhibition (TGI) for both AKT inhibitors alone and in combination with lapatinib are presented in Table 1 for GSK690693 and in S2 Table for
This is consistent with the notion that effective inhibition of PI3K-AKT signaling by lapatinib in HER2+ cells is one of the major requirements for therapeutic response
Summary
Genome aberration targeted therapies promise greater efficacy and fewer potential side effects than traditional chemotherapeutics for the treatment of advanced cancers. The efficacy of single targeted therapeutics has been less than hoped, especially in solid tumors [1, 2] but combination therapies have shown striking synergistic effects in subsets of patients [3,4,5]. This suggests the need to identify patient subsets that will benefit most from specific drug combinations. Combinations of lapatinib with trastuzumab have been shown to be synergistic in both experimental [4] and clinical settings [3], suggesting more complete inhibition of HER2 mediated signaling may be accomplished with combinations of pathway targeted drugs
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