The pan-PI3K inhibitor GDC-0941 activates canonical WNT signaling to confer resistance in TNBC cells: resistance reversal with WNT inhibitor
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Huey-En Tzeng1,5,6,7, Lixin Yang2, Kemin Chen1, Yafan Wang2, Yun-Ru Liu3, Shiow-Lin Pan4, Shikha Gaur1, Shuya Hu1 and Yun Yen1,4
1 Department of Molecular Pharmacology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
2 Translational Research Core Laboratory, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
3 Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan
4 Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
5 Graduate Institute of Clinical Medicine, China Medical University, Taichung, Taiwan
6 Division of Hematology/Oncology, Taichung Veterans General Hospital, Taichung, Taiwan
7 School of Medicine, China Medical University, Taichung, Taiwan
Yun Yen, email:
Lixin Yang, email:
Keywords: pan-PI3K inhibitor, triple-negative breast cancer, PI3K/AKT/mTOR pathway, WNT/beta-catenin pathway, drug resistance
Received: December 16, 2014 Accepted: February 26, 2015 Published: March 14, 2015
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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