The pan-PI3K inhibitor GDC-0941 activates canonical WNT signaling to confer resistance in TNBC cells

Resistance reversal with WNT inhibitor

Huey En Tzeng, Lixin Yang, Kemin Chen, Yafan Wang, Yun Ru Liu, Shiow Lin Pan, Shikha Gaur, Shuya Hu, Yun Yen

研究成果: 雜誌貢獻 › 文章

19 引文 (Scopus)

摘要

The pan-PI3K inhibitors are one treatment option for triple-negative breast cancer (TNBC). However, this treatment is ineffective for unknown reasons. Here, we report that aberrant expression of wingless-type MMTV integration site family (WNT) and activated WNT signals, which crosstalk with the PI3K-AKT-mTOR signaling pathway through GSK3β, plays the most critical role in resistance to pan-PI3K inhibitors in TNBC cells. GDC-0941 is a pan-PI3K inhibitor that activates the WNT/beta-catenin pathway in TNBC cells through stimulation of WNT secretion. GDC-0941-triggered WNT/beta-catenin pathway activation was observed in MDA-MB-231 and HCC1937 cells, which are TNBC cell lines showing aberrant WNT/beta-catenin activation, and not in SKBR3 and MCF7 cells. This observation is further investigated in vivo. GDC- 0941 exhibited minimal tumor inhibition in MDA-MB-231 cells, but it significantly suppressed tumor growth in HER-positive SK-BR3 cells. In vivo mechanism study revealed the activation of WNT/beta-catenin pathway by GDC-0941. A synergistic effect was observed when combined treatment with GDC-0941 and the WNT inhibitor LGK974 at low concentrations in MDA-MB-231 cells. These findings indicated that WNT pathway activation conferred resistance in TNBC cells treated with GDC-0941. This resistance may be further circumvented through combined treatment with pan- PI3K and WNT inhibitors. Future clinical trials of these two inhibitors are warranted.
原文英語
頁（從 - 到）11061-11073
頁數13
期刊Oncotarget
卷6
發行號13
出版狀態已發佈 - 2015

指紋

Triple Negative Breast Neoplasms
Phosphatidylinositol 3-Kinases
beta Catenin
MCF-7 Cells
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
Neoplasms
Clinical Trials
Cell Line
Growth

ASJC Scopus subject areas

  • Oncology

引用此文

The pan-PI3K inhibitor GDC-0941 activates canonical WNT signaling to confer resistance in TNBC cells : Resistance reversal with WNT inhibitor. / Tzeng, Huey En; Yang, Lixin; Chen, Kemin; Wang, Yafan; Liu, Yun Ru; Pan, Shiow Lin; Gaur, Shikha; Hu, Shuya; Yen, Yun.

於: Oncotarget, 卷 6, 編號 13, 2015, p. 11061-11073.

研究成果: 雜誌貢獻 › 文章

Tzeng, HE, Yang, L, Chen, K, Wang, Y, Liu, YR, Pan, SL, Gaur, S, Hu, S & Yen, Y 2015, 'The pan-PI3K inhibitor GDC-0941 activates canonical WNT signaling to confer resistance in TNBC cells: Resistance reversal with WNT inhibitor', Oncotarget, 卷 6, 編號 13, 頁 11061-11073.
Tzeng HE, Yang L, Chen K, Wang Y, Liu YR, Pan SL 等. The pan-PI3K inhibitor GDC-0941 activates canonical WNT signaling to confer resistance in TNBC cells: Resistance reversal with WNT inhibitor. Oncotarget. 2015;6(13):11061-11073.
Tzeng, Huey En ; Yang, Lixin ; Chen, Kemin ; Wang, Yafan ; Liu, Yun Ru ; Pan, Shiow Lin ; Gaur, Shikha ; Hu, Shuya ; Yen, Yun. / The pan-PI3K inhibitor GDC-0941 activates canonical WNT signaling to confer resistance in TNBC cells : Resistance reversal with WNT inhibitor. 於: Oncotarget. 2015 ; 卷 6, 編號 13. 頁 11061-11073.
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abstract = "The pan-PI3K inhibitors are one treatment option for triple-negative breast cancer (TNBC). However, this treatment is ineffective for unknown reasons. Here, we report that aberrant expression of wingless-type MMTV integration site family (WNT) and activated WNT signals, which crosstalk with the PI3K-AKT-mTOR signaling pathway through GSK3β, plays the most critical role in resistance to pan-PI3K inhibitors in TNBC cells. GDC-0941 is a pan-PI3K inhibitor that activates the WNT/beta-catenin pathway in TNBC cells through stimulation of WNT secretion. GDC-0941-triggered WNT/beta-catenin pathway activation was observed in MDA-MB-231 and HCC1937 cells, which are TNBC cell lines showing aberrant WNT/beta-catenin activation, and not in SKBR3 and MCF7 cells. This observation is further investigated in vivo. GDC- 0941 exhibited minimal tumor inhibition in MDA-MB-231 cells, but it significantly suppressed tumor growth in HER-positive SK-BR3 cells. In vivo mechanism study revealed the activation of WNT/beta-catenin pathway by GDC-0941. A synergistic effect was observed when combined treatment with GDC-0941 and the WNT inhibitor LGK974 at low concentrations in MDA-MB-231 cells. These findings indicated that WNT pathway activation conferred resistance in TNBC cells treated with GDC-0941. This resistance may be further circumvented through combined treatment with pan- PI3K and WNT inhibitors. Future clinical trials of these two inhibitors are warranted.",
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AU - Yang, Lixin

AU - Chen, Kemin

AU - Wang, Yafan

AU - Liu, Yun Ru

AU - Pan, Shiow Lin

AU - Gaur, Shikha

AU - Hu, Shuya

AU - Yen, Yun

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N2 - The pan-PI3K inhibitors are one treatment option for triple-negative breast cancer (TNBC). However, this treatment is ineffective for unknown reasons. Here, we report that aberrant expression of wingless-type MMTV integration site family (WNT) and activated WNT signals, which crosstalk with the PI3K-AKT-mTOR signaling pathway through GSK3β, plays the most critical role in resistance to pan-PI3K inhibitors in TNBC cells. GDC-0941 is a pan-PI3K inhibitor that activates the WNT/beta-catenin pathway in TNBC cells through stimulation of WNT secretion. GDC-0941-triggered WNT/beta-catenin pathway activation was observed in MDA-MB-231 and HCC1937 cells, which are TNBC cell lines showing aberrant WNT/beta-catenin activation, and not in SKBR3 and MCF7 cells. This observation is further investigated in vivo. GDC- 0941 exhibited minimal tumor inhibition in MDA-MB-231 cells, but it significantly suppressed tumor growth in HER-positive SK-BR3 cells. In vivo mechanism study revealed the activation of WNT/beta-catenin pathway by GDC-0941. A synergistic effect was observed when combined treatment with GDC-0941 and the WNT inhibitor LGK974 at low concentrations in MDA-MB-231 cells. These findings indicated that WNT pathway activation conferred resistance in TNBC cells treated with GDC-0941. This resistance may be further circumvented through combined treatment with pan- PI3K and WNT inhibitors. Future clinical trials of these two inhibitors are warranted.

AB - The pan-PI3K inhibitors are one treatment option for triple-negative breast cancer (TNBC). However, this treatment is ineffective for unknown reasons. Here, we report that aberrant expression of wingless-type MMTV integration site family (WNT) and activated WNT signals, which crosstalk with the PI3K-AKT-mTOR signaling pathway through GSK3β, plays the most critical role in resistance to pan-PI3K inhibitors in TNBC cells. GDC-0941 is a pan-PI3K inhibitor that activates the WNT/beta-catenin pathway in TNBC cells through stimulation of WNT secretion. GDC-0941-triggered WNT/beta-catenin pathway activation was observed in MDA-MB-231 and HCC1937 cells, which are TNBC cell lines showing aberrant WNT/beta-catenin activation, and not in SKBR3 and MCF7 cells. This observation is further investigated in vivo. GDC- 0941 exhibited minimal tumor inhibition in MDA-MB-231 cells, but it significantly suppressed tumor growth in HER-positive SK-BR3 cells. In vivo mechanism study revealed the activation of WNT/beta-catenin pathway by GDC-0941. A synergistic effect was observed when combined treatment with GDC-0941 and the WNT inhibitor LGK974 at low concentrations in MDA-MB-231 cells. These findings indicated that WNT pathway activation conferred resistance in TNBC cells treated with GDC-0941. This resistance may be further circumvented through combined treatment with pan- PI3K and WNT inhibitors. Future clinical trials of these two inhibitors are warranted.

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