Decoupling of the PI3K pathway via mutation necessitates combinatorial treatment in HER2+ breast cancer [electronic resource]

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Ngôn ngữ: eng

Ký hiệu phân loại: 616.99 Tumors and miscellaneous communicable diseases

Thông tin xuất bản: Berkeley, Calif. : Oak Ridge, Tenn. : Lawrence Berkeley National Laboratory ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2015

Mô tả vật lý: Size: e0133219 : , digital, PDF file.

Bộ sưu tập: Metadata

ID: 261148

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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 (AKT
i
) 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 AKT
i
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, AKT
i
or lapatinib + AKT
i
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
+
/PIK3CA
wt
cells and that lapatinib + AKT
i
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 + AKT
i
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 AKT
i
. This combination does not confer substantial benefit beyond lapatinib in HER2
+
/PIK3CA
wt
cells.

1. 60 applied life sciences
2. Akt signaling cascade
3. Breast cancer
4. Cancer treatment
5. Confidence intervals
6. Drug interactions
7. Drug therapy
8. Mapk signaling cascades
9. Signal inhibition

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