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

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)11061-11073
Number of pages13
JournalOncotarget
Volume6
Issue number13
Publication statusPublished - 2015

Fingerprint

Triple Negative Breast Neoplasms
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2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
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Keywords

  • Drug resistance
  • Pan-PI3K inhibitor
  • PI3K/AKT/mTOR pathway
  • Triple-negative breast cancer
  • WNT/beta-catenin pathway

ASJC Scopus subject areas

  • Oncology

Cite this

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.

In: Oncotarget, Vol. 6, No. 13, 2015, p. 11061-11073.

Research output: Contribution to journalArticle

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. In: Oncotarget. 2015 ; Vol. 6, No. 13. pp. 11061-11073.
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