MAPK4 promotes triple negative breast cancer growth and reduces tumor sensitivity to PI3K blockade

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.

On the therapeutic potential of MAPK4 in triple-negative breast cancer

“…Compared to ERK3, which is expressed in most tissues and cell lines, ERK4 shows a more restricted expression profile and is generally found at low or undetectable levels in most cell lines. Previous independent observations from our laboratories suggested that ERK4 is not expressed in some of the MAPK4-high cell lines described in Wang et al 4 paper, prompting us to examine in more detail the expression of ERK4 in their cell line panel. We first measured the abundance of MAPK4 mRNA by quantitative RT-PCR.…”

“…To investigate the role of ERK4 in TNBC, Wang et al 4 first surveyed a panel of TNBC cell lines and found that ERK4 is highly expressed in MDA-MB-231, Hs578T and HCC1937 cell lines (referred to as MAPK4-high), while other TNBC cell lines express low-to-undetectable levels of the kinase. They used the NSCLC cell line H1299 as a positive control of ERK4 expression.…”

“…The activation loop threonine of AKT1, AKT2 and AKT3 (Thr308 in AKT1) is not followed by a proline, raising questions about the validity and significance of this mechanism. In experiments performed prior to publication of the Wang et al 4 study, we have examined the ability of ERK4 to phosphorylate AKT on Thr308 and Ser473 in HEK 293T cells. We found that overexpression of either ERK4 or catalytically-inactive ERK4 KK49/50AA had no significant impact on the phosphorylation of AKT on its activating phosphorylation sites Thr308 and Ser473 (Fig.…”

“…Interestingly, recent work has suggested that ERK4 promotes prostate cancer progression via the non-canonical activation of AKT/mTOR signaling 2,3 . In their recent study, Wang et al 4 report that ERK4 is expressed in a subset of triple-negative breast cancer (TNBC) cell lines and that this expression is critical for AKT activation and for sustaining TNBC cell proliferation in vitro and tumor growth in mice. They also show that depletion of ERK4 sensitizes TNBC cells to phosphatidylinositol-3-kinase (PI3K) inhibitors.…”

“…some of the MAPK4-high cell lines described in Wang et al 4 paper, prompting us to examine in more detail the expression of ERK4 in their cell line panel. We first measured the abundance of MAPK4 mRNA by quantitative RT-PCR.…”