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

ERK3/MAPK6 (MAPK6 gene) along with its paralog ERK4/MAPK4 (MAPK4 gene) define a distinct subfamily of atypical mitogen-activated protein kinases (MAPKs)1. Much remains to be learned about the substrates and biological functions of these signaling enzymes. Interestingly, recent work has suggested that ERK4 promotes prostate cancer progression via the non-canonical activation of AKT/mTOR signaling2,3. 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. They conclude that ERK4 is a promising therapeutic target for TNBC and has potential for combination therapy with PI3K inhibitors. Here, we raise concerns about the cellular models and experimental approaches used in this study, which compromises the conclusions on the oncogenic role of ERK4 in TNBC.