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

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.

• Authors: Huey-En Tzeng, Lixin Yang, Kemin Chen, Yafan Wang, Yun-Ru Liu, Shiow-Lin Pan, Shikha Gaur, Shuya Hu, Yun Yen
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 13 Pg. 11061-73 (May 10 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25857298 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
• Indazoles
• Phosphoinositide-3 Kinase Inhibitors
• Pyrazines
• Pyridines
• RNA, Messenger
• Sulfonamides
• Wnt Proteins
• beta Catenin
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• LGK974

Topics

• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Female
• Fluorescent Antibody Technique
• Humans
• Indazoles (pharmacology)
• Mice
• Mice, Nude
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Pyrazines (pharmacology)
• Pyridines (pharmacology)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Sulfonamides (pharmacology)
• TOR Serine-Threonine Kinases (genetics, metabolism)
• Triple Negative Breast Neoplasms (drug therapy, metabolism, pathology)
• Tumor Cells, Cultured
• Wnt Proteins (antagonists & inhibitors, genetics, metabolism)
• Xenograft Model Antitumor Assays
• beta Catenin (genetics, metabolism)