Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=25857298
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
The pan-PI3K inhibitor GDC-0941 activates canonical WNT signaling to confer
resistance in TNBC cells: resistance reversal with WNT inhibitor
#MMPMID25857298
Tzeng HE
; Yang L
; Chen K
; Wang Y
; Liu YR
; Pan SL
; Gaur S
; Hu S
; Yen Y
Oncotarget
2015[May]; 6
(13
): 11061-73
PMID25857298
show ga
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 GSK3?, 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.
free
free
free
