Of the four mammalian MAP kinase pathways (ERK1/2, JNK, p38 and BMK1), BMK1 is the least studied. BMK1 and ERK1/2 pathways are both activated by mitogens and oncogenic signals and are therefore implicated in tumorigenesis. Indeed, the ERK1/2 pathway has received significant attention for the development of chemotherapeutic drugs. Deregulated BMK1 activity has been associated with a variety of human malignancies including chemoresistance of breast tumours, metastasis of prostate tumour cells and tumour-associated angiogenesis. Conditional knockout of endothelial BMK1 in mice, however, led to lethal vascular instability, discouraging exploration of BMK1 as a therapeutic target.
A new study from scientists at the Scripps Research Institute has revealed more detail on the role of BMK1 in oncogenesis and suggests that BMK1 inhibition could be a viable therapeutic strategy. The study found that BMK1 is associated with the tumour suppressor, PML (promyelocytic leukemia protein), and suppresses its anti-cancer activity. In cellular studies, reduced expression of BMK1 resulted in induced expression of p21, a downstream effector of PML and modulator of cell proliferation.
The team’s serendipitous discovery of a selective inhibitor of BMK1, XMD8-92, permitted further studies in animal models. XMD8-92 significantly inhibited the growth of xenografted human tumours in mice, with no obvious adverse effects. More specifically, in contrast to the BMK1 conditional knockout studies, no vascular instability was observed in response to pharmacological inhibition of BMK1.
The study is published in Cancer Cell.