Abstract
About 15–20% of breast cancer (BCa) is triple-negative BCa (TNBC), a devastating disease with limited therapeutic options. Aberrations in the PI3K/PTEN signaling pathway are common in TNBC. However, the therapeutic impact of PI3K inhibitors in TNBC has been limited and the mechanism(s) underlying this lack of efficacy remain elusive. Here, we demonstrate that a large subset of TNBC expresses significant levels of MAPK4, and this expression is critical for driving AKT activation independent of PI3K and promoting TNBC cell and xenograft growth. The ability of MAPK4 to bypass PI3K for AKT activation potentially provides a direct mechanism regulating tumor sensitivity to PI3K inhibition. Accordingly, repressing MAPK4 greatly sensitizes TNBC cells and xenografts to PI3K blockade. Altogether, we conclude that high MAPK4 expression defines a large subset or subtype of TNBC responsive to MAPK4 blockage. Targeting MAPK4 in this subset/subtype of TNBC both represses growth and sensitizes tumors to PI3K blockade.
Highlights
About 15–20% of breast cancer (BCa) is triple-negative BCa (TNBC), a devastating disease with limited therapeutic options
Analysis of 817 gene expression profiles in The Cancer Genome Atlas (TCGA)[17] revealed that MAPK4 expression is elevated in 30% or more of basal-like BCa (Fig. 1a), 70–80% of which are TNBC18–23
Profiling human tumors show that MAPK4 is highly expressed in a large subset of TNBC
Summary
About 15–20% of breast cancer (BCa) is triple-negative BCa (TNBC), a devastating disease with limited therapeutic options. We demonstrate that a large subset of TNBC expresses significant levels of MAPK4, and this expression is critical for driving AKT activation independent of PI3K and promoting TNBC cell and xenograft growth. The ability of MAPK4 to bypass PI3K for AKT activation potentially provides a direct mechanism regulating tumor sensitivity to PI3K inhibition. We recently reported that MAPK4 is a key oncogenic kinase promoting cancer via non-canonical activation of AKT/mTOR independent of PI3K/PDK116. Knockdown/knockout of MAPK4 in the MAPK4-high TNBC cells and xenografts sensitized them to PI3K inhibition. These results identify MAPK4 as a promising therapeutic target for TNBC and its potential in combined therapy with PI3K inhibition
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